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Exercise enhances wound healing and prevents cancer progression during aging by targeting macrophage polarity

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Abstract

Physical activity, which can include regular and repetitive exercise training, has been shown to decrease the incidence of age-related diseases. Aging is characterized by aberrant immune responses, including impaired wound healing and increased cancer risk. The behavior and polarized phenotype of tissue macrophages are distinct between young and old organisms. The balance of M1 and M2 macrophages is altered in the aged tissue microenvironment, with a tilt towards an M2-dominant macrophage population, as well as its associated signalling pathways. These M2-type responses may result in unresolved inflammation and create an environment that impairs wound healing and is favorable for cancer growth. We discuss the concept that exercise training can improve the regulation of macrophage polarization and normalize the inflammatory process, and thereby exert anticancer effects and enhance wound healing in older humans.

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... A study done in C57BLBJ mice found that exercise enhanced skeletal muscle insulin sensitivity by promoting influx of M2 macrophages [67]. Several studies in diet-induced obese mice have demonstrated that exercise inhibits inflammation in adipose tissue by suppressing macrophage infiltration and by accelerating phenotypic switching from M1 to M2 macrophages [68][69][70]. ...
... The author recommends that health care givers prescribe exercise to all eligible adults in the following manner: 1. Calculate the patient's maximum heart rate (MHR) using the formula MHR = 220-age; 2. Have the patient start exercising at 40-50% of MHR and then gradually increase the level to 70 ...
... It has also been used clinically for various types of cancers including breast cancer [3], and recently has been shown to enhance healthy aging in animal models [4,5]. In this regard it is of interest to see if additional intervention approaches can be combined with rapamycin [6]. Regular physical exercise is associated with healthy aging and reduced risk of age-related diseases, such as cancer. ...
... CB6F1 (BALB/c x C57BL/6) females at 4 months of age were started on rapamycin medicated chow 14 ppm [4] or control chow (5lG6) in cohorts of 20 each. One week later, 10 mice in each cohort were given access to freely rotating wheels (Med Associates ENV-044, Vermont), or to wheels that were locked, as described [6,7]. After 10 days, mice were injected with 1 × 10 4 4T1 mammary tumor cells into the 4 th mammary fat pad and allowed to continue running for another 17 days. ...
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Rapamycin is an immunosuppressive and anti-cancer drug recently shown to enhance healthy aging in animal models. Regular physical exercise is associated with healthy aging and reduced risk of age-related diseases, such as cancer. In order to test the combined effect of these approaches, mice with 4T1 breast cancer were fed rapamycin at 14 ppm and allowed access to voluntary running wheels. After 17 days of treatment, mice fed the rapamycin diet that ran showed a significant increase in tumor burden compared with mice that did not run (P = 0.017). Not only does this have implications for young breast cancer patients, but suggests that combining rapamycin and exercise as an anti-aging strategy at a young age might be contraindicated.
... The initial functional state of immune cells in turn depends on many factors that are rarely appreciated in the treatment regimen such as treatment time and condition of the patients (inpatient vs outpatient setting). Numerous studies have demonstrated that even moderate physical exercise modulates the functional response of immune cells, including monocytes and granulocytes and affects cytokine generation, reactive oxygen (ROS) and nitrogen species production, and chemotaxis and phagocytosis of these cells [16][17][18][19][20]. It is widely reported that therapeutic effects can be markedly improved by administering a drug taking into account the rhythm of cell functions [21][22][23][24][25]. Treatment with NSC631570 is carried out in the morning in both inpatient (associated with limited excursion) and outpatient settings (associated with moderate physical activity). ...
... Physical activity is a systemic phenomenon with impact on immune cell function. The effect of physical activity on immune cells depends on its intensity and regimen as well as participant age [17,20]. Of innate immune system cells, neutrophils and macrophages appear to be most responsive to the influence of physical activity, both in terms of numbers and function. ...
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To evaluate the effect of moderate physical exercise and treatment time on the organism's response to NSC631570. The sensitivity of circulating phagocytes to the drug at different times of day was estimated in in vitro experiments. NSC631570 was administered intravenously to healthy volunteers (eleven men, 23 ± 2 years) in a single therapeutic dose in an inpatient and outpatient setting. Blood samples were obtained before the drug administration, 30 min after the drug injection and every fourth hour through 24 hour period. Biochemical parameters were determined using the hematological analyzer. Flow cytometry was used to evaluate phagocyte metabolism. Treatment of circulating phagocytes with NSC631570 in vitro resulted in an increase in ROS production along with a decrease in their phagocytic activity, most expressed in the morning time. Drug injection to sedentary persons resulted in pro-inflammatory metabolic polarization of circulating phagocytes. Introduction of NSC631570 to active persons was accompanied by a significant increase in phagocyte endocytosis along with a decrease in the daily mean of ROS generation. Significant oscillation (but in the normal ranges) of urea, creatinine, alanine aminotransferase and aspartate aminotransferase after NSC631570 introduction in outpatient setting was shown during the day. Physical activity interferes with immunomodulatory action of NSC631570 and abrogates pro-inflammatory shift of circulating phagocytes. Biochemical parameters of blood from patients treated with NSC631570 in outpatient setting must be interpreted cautiously considering the effect of physical activity on some metabolic biomarkers.
... A study done in C57BLBJ mice found that exercise enhanced skeletal muscle insulin sensitivity by promoting influx of M2 macrophages [67]. Several studies in diet-induced obese mice have demonstrated that exercise inhibits inflammation in adipose tissue by suppressing macrophage infiltration and by accelerating phenotypic switching from M1 to M2 macrophages [68][69][70]. ...
... The author recommends that health care givers prescribe exercise to all eligible adults in the following manner: 1. Calculate the patient's maximum heart rate (MHR) using the formula MHR = 220-age; 2. Have the patient start exercising at 40-50% of MHR and then gradually increase the level to 70 ...
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... Physical resilience, defined as the ability of an organism to respond and quickly resolve physical stress, can be measured at younger ages [1] by various types of stressors, for example increased skeletal muscle activity during exercise. Voluntary wheel running by mice is a mildly stressful physical activity that is easily quantifiable [2,3]. We hypothesized that short term voluntary wheel running would align, in an age-related manner, with melanoma tumor behavior. ...
... Wheels were locked for two days to allow for acclimation, and then unlocked for three days to measure running activity. Mice were returned to their group cages and held for three months to decrease the possibility of any anti-tumor effect of wheel running [3]. Mice were then injected with 5 × 10 5 B16F0 melanoma tumor cells (ATCC) subcutaneously into the left inguinal space and the right axillary space as previously described (Pettan Brewer et al., 2012). ...
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Aging intervention studies are hampered by the lack of predictive measures for determination of individuals at risk of age-associated chronic disease. Assessment of physical resilience could be informative in this regard, especially for age-related diseases such as cancer. Voluntary wheel running is a mildly stressful physical activity that is easily quantifiable in the mouse but has not been studied as a predictor of resistance to tumor invasiveness with increasing age. Male C57BL/6 mice in cohorts of 4, 12, 20, and 28 months of age were allowed access to a slanted in-cage running wheel for 3 days. Three months later, mice were injected subcutaneously with B16 melanoma tumor cells and followed for two weeks before harvesting. No relation was observed between running distance and tumor burden in the 4-month age group. The 12-month age group showed a trend, and the 20- and 28-month age groups showed a negative correlation (P < 0.05) between running distance and tumor burden. Mice in the 20-month age group that ran longer distances had lower tumor invasive scores compared to mice in the same age group that ran shorter distances. In conclusion, short term exercise capability could be a marker for resilience to cancer, and possibly other age-related disease conditions, in mice.
... These numerical changes coincide with altered signalling via some toll-like receptors resulting in impaired cytokine production. Changes in monocytes due to age per se are thought to be mirrored by the phenotype and functional properties of tissue macrophages, whereby classically activated M1 cells decline and alternatively activated M2 cells accumulate [17]. However, the composition of tissue-resident cells is complicated by adipose tissue accumulation and dysfunction-dominated by M1 macrophages [18,19]-and the M1/M2 paradigm is likely to be an oversimplification [20,21]. ...
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Moderate intensity aerobic exercise training or regular physical activity is beneficial for immune function. For example, some evidence shows that individuals with an active lifestyle exhibit stronger immune responses to vaccination compared to those who are inactive. Encouragingly, poor vaccine responses, which are characteristic of an ageing immune system, can be improved by single or repeated bouts of exercise. In addition, exercise-induced lymphocytosis, and the subsequent lymphocytopenia, is thought to facilitate immune surveillance, whereby lymphocytes search tissues for antigens derived from viruses, bacteria, or malignant transformation. Aerobic exercise training is anti-inflammatory and is linked to lower morbidity and mortality from diseases with infectious, immunological, and inflammatory aetiologies, including cancer. These observations have led to the view that aerobic exercise training might counter the age-associated decline in immune function, referred to as immunosenescence. This article summarises the aspects of immune function that are sensitive to exercise-induced change, highlighting the observations which have stimulated the idea that aerobic exercise training could prevent, limit, or delay immunosenescence, perhaps even restoring aged immune profiles. These potential exercise-induced anti-immunosenescence effects might contribute to the mechanisms by which active lifestyles reduce the risk of developing cancer and perhaps benefit patients undergoing cancer therapy.
... There are a number of possible explanations for this more rapid decrease in wound size in the LEX mice, including a change in the balance of pro-inflammatory versus anti-inflammatory cytokines in the wound environment. 22 Another potential reason the investigators hope to explore further in future studies is the effect of exercise on macrophage function and polarization 23,24 (ie, M1 to M2 shift). The role of exercise in altering markers of oxidative stress and angiogenesis also could provide valuable insight into these effects. ...
Article
Introduction: Moderate-intensity aerobic exercise has been noted to improve wound healing rates in mice and people, but different intensities of exercise may have different impacts on healing rates. It is important to determine the most beneficial exercise intensity for improving wound healing in people with type 2 diabetes to help prevent wounds from becoming chronic, greatly reduce pain and immobility, and lower the high cost of health care associated with treatment. Objective: The purpose of this study is to determine the impact of low-intensity exercise compared with high-intensity exercise in terms of the rate of wound healing in diabetic mice. Materials and methods: Twenty-one 10-week-old female diabetic mice were randomly assigned to a sedentary control group (CON), low-intensity treadmill exercise (LEX) group, or high-intensity treadmill exercise (HEX) group. Mice were exercised for 30 minutes, 5 days per week, for 3 weeks. Mice were wounded on their upper back with a 3.5-mm punch biopsy instrument, and wounds were photographed at the same time every day. Results: In terms of the length of time it took wounds to fully heal, CON mice healed in an average of 14.4 ± 2.4 days (number of days to decrease to less than 10% of their original size ± standard deviation) and HEX mice in 14.0 ± 3.0 days (P = .396). However, LEX mice healed faster than CON in an average of 10.1 ± 2.3 days (P = .004). Conclusions: In this preliminary investigation, low-intensity exercise accelerated wound healing rates in diabetic mice but high-intensity exercise did not. Future studies should investigate the mechanisms behind this effect and evaluate different intensities of exercise on wound healing in humans with type 2 diabetes.
... Indeed, a recent study in melanoma (48) demonstrated that voluntary exercise increased NK cell infiltration in the tumor that correlated with a decrease in tumor growth rate. In addition to NK cells, data published on the influence of exercise on macrophages (49) indicate that regular exercise can result in M1 macrophage polarization and better wound healing, thus promoting an antitumor response. ...
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An imbalance in oxygen delivery-to-demand in solid tumors results in local areas of hypoxia leading to poor patient prognosis. We hypothesize that aerobic exercise increases tumor blood flow, recruits previously non-perfused tumor blood vessels and thereby augments blood-tumor O2 transport and diminishes tumor hypoxia. When combined with conventional anti-cancer treatments, aerobic exercise can significantly improve the outcomes for several types of cancers.
... Recently, a number of animal and human studies in aged and obese populations have indicated that exercise may be able to play a role in supporting wound healing. [3][4][5] Even in the absence of direct DFU benefit, exercise would provide other diabetes-related benefits to patients with DFUs. [6][7][8] However, the etiology of DFUs makes exercise a challenge for these patients. ...
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Background: Offloading devices for diabetic foot ulcers (DFU) generally restrict exercise. In addition to traditional health benefits, exercise could benefit DFU by increasing blood flow and acting as thermotherapy. This study functionally evaluated a cycling cleat designed for forefoot DFU. Methods: Fifteen individuals at risk of developing a DFU used a recumbent stationary bicycle to complete one 5-minute cycling bout with the DFU cleat on their study foot and one 5-minute bout without it. Foot stress was evaluated by plantar pressure insoles during cycling. Laser Doppler perfusion monitored blood flow to the hallux. Infrared photographs measured foot temperature before and after each cycling bout. Results: The specialized cleat significantly reduced forefoot plantar pressure (9.9 kPa versus 62.6k Pa, P < .05) and pressure time integral (15.4 versus 76.4 kPa/sec, P < .05). Irrespective of footwear condition, perfusion to the hallux increased (3.97 ± 1.2 versus 6.9 ± 1.4 tissue perfusion units, P < .05) after exercise. Infrared images revealed no changes in foot temperature. Conclusions: The specialized cleat allowed participants to exercise with minimal forefoot stress. The observed increase in perfusion suggests that healing might improve if patients with active DFU were to use the cleat. Potential thermotherapy for DFU was not supported by this study. Evaluation of the device among individuals with active DFU is now warranted.
... Interestingly, sustained overexpression of PGC-1α in muscle stimulates macrophage infiltration, as demonstrated by the higher number of tissue-resident macrophages in muscles of MCKα mice with a predominant M2 phenotype 16,17 . Muscle PGC-1α could thereby be indicative of the higher resistance of trained muscle fibers against damage and the more efficient repair and regeneration process 18,19 in a physiological context with consistently elevated PGC-1α gene expression. Indeed, the higher proliferative rate of satellite cells in MCKα mice further supports this hypothesis 15 . ...
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Activation of resident and infiltrating immune cells is a central event in training adaptation and other contexts of skeletal muscle repair and regeneration. A precise orchestration of inflammatory events in muscle fibers and immune cells is required after recurrent contraction-relaxation cycles. However, the mechanistic aspects of this important regulation remain largely unknown. We now demonstrate that besides a dominant role in controlling cellular metabolism, the peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) also has a profound effect on cytokine expression in muscle tissue. Muscle PGC-1α expression results in activation of tissue-resident macrophages, at least in part mediated by PGC-1α-dependent B-type natriuretic peptide (BNP) production and secretion. Positive effects of exercise in metabolic diseases and other pathologies associated with chronic inflammation could accordingly involve the PGC-1α-BNP axis and thereby provide novel targets for therapeutic approaches.
... Due to the low number of neutrophils in liver and kidney tissue in the immunohistochemical results, we chose the ratio of IFN-γ/IL-4 and IL-2/IL-10 as markers (Xiang et al. 2014;Goh and Ladiges 2014), which are commonly used to determine the direction of the inflammatory balance of immune cells. The two ratios were equally reduced after fluoride exposure. ...
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With the intensification of environmental pollution, the content of fluoride is increasing in human and animal living environments. Long-term fluoride exposure can cause damage to the liver and kidney, which are the main sites for fluoride metabolism, storage and removal. Moreover, exercise often accompanies the entire process of fluoride exposure in humans and animals. However, the mechanism of exercise on fluoride-induced liver and kidney injury remains unclear. Hence, we established a fluoride exposure and/or exercise mouse model to explore the influence of exercise on fluoride-induced liver and kidney inflammation and the potential mechanism. The results showed that fluoride caused obvious structural and functional damage and the notable recruitment of immunocytes in the liver and kidney. In addition, fluoride increased the levels of IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL-13, IL-21, TNF-α, and TGF-β but decreased the ratio of IFN-γ/IL-4 and IL-2/IL-10, which indicated that fluoride disturbed the inflammatory balance and caused hepatonephritis. In addition, the expression levels of IKKβ and NFκB were increased, and the expression of IκBα was decreased after fluoride exposure, indicating that fluoride activated the IKKβ/NFκB pathway. In summary, long-term moderate treadmill exercise relieved fluoride-induced liver and kidney inflammatory responses through the IKKβ/NFκB pathway, and exercise can be used to prevent fluoride-induced liver and kidney damage.
... 50 Egzersizin NK hücre sito-toksik aktivasyonu artırdığı, monosit ve makrofaj fonksiyonu ve sayısını artırdığı, artmış antijen sunumu inflamasyonu azalttığı, proinflamatuar monosit oranında azalma sağladığı CD8 T hücre oranını artırdığı ve yaşlı T hücrelerinin birikimini önlediği gösterilmiştir. [51][52][53][54][55][56] Ayrıca iskelet kasından myokin sekresyonunun egzersizin koruyucu etkisinden sorumlu olabileceği düşünülmektedir. 57 Oncostatin M'nin ümit verici hedef olduğu düşünülmektedir. ...
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nümüzde kanser önlenmesi ve tedavi stratejisi ile ilgili bir çok çalışma far-makolojik tedaviler dışında yeni yaklaşımların arayışına yönelmiştir. Son yıllarda kanser önlenmesinde yaşam kalitesini de düzeltebilen diyet ve eg-zersiz gibi konular araştırmaların odaklandığı konular olmuştur. Uzun yıllardır fi-ziksel aktivitenin kardiyovasküler hastalık, diabet, hipertansiyon ve metabolik sendrom gibi yaşla ilişkili kronik hastalıkların insidansında azalma sağladığı bilin-mektedir. Son yıllarda yapılan çalışmalar egzersizin kanser hastalığının önlenme-sinde de yarar sağladığını göstermiştir. Bu çalışmalar özellikle kolorektal kanser ve meme kanseri hastalarında yoğunlaşmıştır. M Me em me e K Ka an ns se er ri i v ve e E Eg gz ze er rs si iz zi in n ö ön nl le ey yi ic ci i e et tk ki is si i: : Adolesan dönemde yapılan fizik-sel aktivitenin premenopozal meme kanserine karşı koruyucu olduğu görünmekte-dir. 63 786 meme kanser vakasından oluşan 31 prospektif kohort çalışmayı Turkiye Klinikleri J Med Oncol-Special Topics 2016;9(3) 45 Kanser ve Egzersiz Ö ÖZ ZE ET T Son yıllarda egzersizin kanser önlenmesi ve kanser hastalarının sonuçları üzerine etkisi ile ilgili birçok çalışma yapılmıştır. Bu çalışmalar özellikle kolorektal kanser ve meme kanseri hasta-larında yoğunlaşmıştır. Çalışma sonuçlarına dayanarak diyet ve egzersizdeki iyileştirmeyi sağlayan yaşam stili müdahaleleri hem bazı kanserlerin önlenmesinde hem de kanserin ve tedavisinin olum-suz etkilerini düzeltmede etkili bir yol olarak önerilmektedir. Egzersiz ve kanser ilişkisinin mole-küler mekanizmasını araştıran çalışmalar devam etmektedir. A An na ah ht ta ar r K Ke el li im me el le er r: : Egzersiz; önleme ve kontrol; kaşeksi A AB BS ST TR RA AC CT T In recent years, a lot of studies have been done about the prevention from cancer via exercise and its effects on the results of the cancer patients. These studies are particularly concentrated on the colorectal cancer and breast cancer patients. Depending on the results of these studies , the interventions in lifestyle which provide better diet and exercise programme is suggested to be an affective way in both preventing from certain cancer types and restoring the negative impacts of the cancer treatment. The studies which investigate the molecular mechanism of the relation between exercise and cancer is being continued. K Ke ey y W Wo or rd ds s: : Exercise; prevention and control; cachexia T Tu ur rk ki iy ye e K Kl li in ni ik kl le er ri i J J M
... Exercise is an emerging pro-myelination therapeutic intervention for many pathologies including demyelinating disease (Sampaio-Baptista et al., 2013;Scholz et al., 2009) and is associated with elevated BDNF levels and increased neuronal activity (Gold et al., 2003). Exercise can shift macrophage polarization from an M1 to an M2 state (Goh and Ladiges, 2014;Macpherson et al., 2015) and be used as a preemptive strategy to mitigate demyelinating disease (Bernardes et al., 2016). Whether it has an identical molecular signature and impact as direct nerve stimulation remains to be determined, but is promising as a non-interventional adjunct therapy. ...
Article
Demyelinating peripheral nerves are infiltrated by cells of the monocyte lineage, including macrophages, which are highly plastic, existing on a continuum from pro-inflammatory M1 to pro-repair M2 phenotypic states. Whether one can therapeutically manipulate demyelinated peripheral nerves to promote a pro-repair M2 phenotype remains to be elucidated. We previously identified brief electrical nerve stimulation (ES) as therapeutically beneficial for remyelination, benefits which include accelerated clearance of macrophages, making us theorize that ES alters the local immune response. Thus, the impact of ES on the immune microenvironment in the zone of demyelination was examined. Adult male rat tibial nerves were focally demyelinated via 1% lysophosphatidyl choline (LPC) injection. Five days later, half underwent 1 hour 20 Hz sciatic nerve ES proximal to the LPC injection site. ES had a remarkable and significant impact, shifting the macrophage phenotype from predominantly pro-inflammatory/M1 toward a predominantly pro-repair/M2 one, as evidenced by an increased incidence of expression of M2-associated phenotypic markers in identified macrophages and a decrease in M1-associated marker expression. This was discernible at 3 days post-ES (8 days post-LPC) and continued at the 5 day post-ES (10 days post-LPC) time point examined. ES also affected chemokine (C-C motif) ligand 2 (CCL2; aka MCP-1) expression in a manner that correlated with increases and decreases in macrophage numbers observed in the demyelination zone. The data establish that briefly increasing neuronal activity favorably alters the immune microenvironment in demyelinated nerve, rapidly polarizing macrophages toward a pro-repair phenotype, a beneficial therapeutic concept that may extend to other pathologies. GLIA 2016.
... Other possible and perspective approaches might be related to nutritional intervention on patients or physical exercise. Indeed, it has been demonstrated that retinoic acid [114] and physical exercise [115,116] affect macrophage metabolism/phenotype, cytokines/chemokines expression, overall immune response, and wound healing. The three main approaches for immunemodulation have been summarized in a reduced view in Fig. 4. ...
Article
Tissue engineering (TE) for tissue and organ regeneration or replacement is generally performed with scaffold implants, which provide structural and molecular support to in vitro seeded or in vivo recruited cells. TE implants elicit the host immune response, often resulting in engraftment impediment or rejection. Besides this negative effect, however, the immune system components also yield a positive influence on stem cell recruitment and differentiation, allowing tissue regeneration and healing. Thus, a balanced cooperation between pro-inflammatory and pro-resolution players of the immune response is an essential element of implant success. In this context, macrophage plasticity plays a fundamental role. Therefore modulating the immune response, instead of immune suppressing the host, might be the best way to successfully implant TE tissues or organs. In particular, it is becoming evident that the scaffold, immune and stem cells are linked by a three-way interaction, and many efforts are being made for scaffold-appropriate design and functionalization in order to drive the inflammation process towards regeneration, vascularization and implant success. This review discusses current and potential strategies for inflammation modulation to aid engraftment and regeneration, supporting the concept that quality, and not quantity, of inflammation might influence implant success. This article is protected by copyright. All rights reserved.
... In cancer, both in the presence or not of cachexia, exercise consistently improves the quality of life by inducing significant alterations on body composition, metabolism, and chronic inflammation. There is a robust body of evidence demonstrating that nonexhaustive physical exercise may influence all aspects related with the emergence [7,8], progression [9,10], and outcome of cancer [11][12][13]. ...
Article
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Purpose of review: To discuss the role of physical exercise in the attenuation of cancer cachexia-associated symptoms, and upon the outcome of chemotherapy, with special focus on the anti-inflammatory role of chronic exercise. Recent findings: The review addresses the recent findings regarding the positive effects of endurance and strength exercise training upon metabolic dysfunction, systemic inflammation and body composition alterations in the syndrome of cachexia. The employment of different exercise protocol strategies, in respect to intensity, duration, work load and in concomitance with pharmacological treatment is considered. Summary: Cachexia is a multifactorial wasting syndrome afflicting patients with cancer, chronic obstructive pulmonary disease, chronic heart failure, trauma, among other diseases. This condition markedly compromises the quality of life, treatment outcome and survival. Recent literature indicates an unequivocal role of chronic exercise in modulating cachexia and other cancer-associated dysfunctions. Exercise is proposed as a complementary treatment in cancer, and represents a function-preserving, anti-inflammatory and metabolism-modulating strategy with low cost, and high versatility and availability. Furthermore, exercise decreases cancer recurrence and presents a positive impact on public health management, reducing hospitalization and medication costs.
... Concerning the possible mechanisms of action at the cellular level, exercise can improve the regulation of macrophage polarization and the inflammatory process, and improve wound healing in older people with cancer [20] Exercise also induces changes at the cytokine level and affects epigenetic patterns and activity of tumor-competitive lymphocytes [21] During exercise, tumor perfusion increases and tumor hypoxia decreases, which reduces vasoconstriction. Exercise may also enhance the delivery of tumor-targeting drugs and modulate the normally hypoxic microenvironment within a tumor and thus lead to a less aggressive phenotype [22]. ...
... Monocyte numbers are stable with aging, but classical cells (CD14 ++ CD16 − ) decline, and intermediate (CD14 + CD16 + ) and non-classical (CD14 + CD16 ++ ) cells increase, but overall, monocyte cytokine production is impaired (170,172). These changes with blood monocytes are thought to be mirrored by tissue-resident macrophages, whereby classically activated M1 cells decline, and alternatively activated M2 cells accumulate (173). However, alterations in tissue-resident cells with advancing age are very likely to be a result of adipose tissue accumulation and dysfunction that also occurs in parallel with aging (174,175). ...
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Epidemiological evidence indicates that regular physical activity and/or frequent structured exercise reduces the incidence of many chronic diseases in older age, including communicable diseases such as viral and bacterial infections, as well as non-communicable diseases such as cancer and chronic inflammatory disorders. Despite the apparent health benefits achieved by leading an active lifestyle, which imply that regular physical activity and frequent exercise enhance immune competency and regulation, the effect of a single bout of exercise on immune function remains a controversial topic. Indeed, to this day, it is perceived by many that a vigorous bout of exercise can temporarily suppress immune function. In the first part of this review, we deconstruct the key pillars which lay the foundation to this theory—referred to as the “open window” hypothesis—and highlight that: (i) limited reliable evidence exists to support the claim that vigorous exercise heightens risk of opportunistic infections; (ii) purported changes to mucosal immunity, namely salivary IgA levels, after exercise do not signpost a period of immune suppression; and (iii) the dramatic reductions to lymphocyte numbers and function 1–2 h after exercise reflects a transient and time-dependent redistribution of immune cells to peripheral tissues, resulting in a heightened state of immune surveillance and immune regulation, as opposed to immune suppression. In the second part of this review, we provide evidence that frequent exercise enhances—rather than suppresses—immune competency, and highlight key findings from human vaccination studies which show heightened responses to bacterial and viral antigens following bouts of exercise. Finally, in the third part of this review, we highlight that regular physical activity and frequent exercise might limit or delay aging of the immune system, providing further evidence that exercise is beneficial for immunological health. In summary, the over-arching aim of this review is to rebalance opinion over the perceived relationships between exercise and immune function. We emphasize that it is a misconception to label any form of acute exercise as immunosuppressive, and, instead, exercise most likely improves immune competency across the lifespan.
... Part of the protective effect of exercise is related to changes in immune function, which may improve various aspects of wound healing, including macrophage polarization and functional status. Regular exercise has also been documented to be associated with reduced cancer risk and delayed tumor progression 8 . Exercise training interventions in previously sedentary elderly individuals have been shown to enhance T-cell proliferative capacity 9,10 . ...
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Background Aging is characterized with immunosenescence associated with a hyper-inflammatory state, characterized by elevated circulating levels of pro-inflammatory mediators. Physical exercise is a potential strategy for improving the immune system dysfunction and chronic inflammation that accompanies aging. However, there is a need to differentiate between aerobic and resistance exercise training regarding human immune system and systemic inflammation among the elderly Saudi population. Objective The aim of this study was to compare the impact of 6 months of aerobic versus resisted exercise training on inflammatory cytokines and immune system response among elderly. Material and methods Sixty previously sedentary elderly subjects participated in this study, their age ranged from 61–66 years. All Subjects were randomly assigned to supervised aerobic exercise intervention group (group A, n=40) or resistance exercise group (group B, n=40). Number of CD3⁺,CD4⁺,CD8⁺ T cells count and CD4/CD8 ratio were quantified, IL-6, TNF-α and IL10 were measured before and after 6 months, at the end of the study. Results The mean values of CD3⁺, CD4⁺ and CD8⁺ T cells count and IL-10 were significantly increased, whereas the mean values of CD4/CD8 ratio, IL-6 and TNF-α were significantly decreased in group (A) and group (B). Also; there were significant differences between mean levels of the investigated parameters in group (A) and group (B) after treatment. Conclusion The current study provides evidence that aerobic exercise is more appropriate in modulating the immune system and inflammatory markers among the elderly population.
... 54 Additionally, deficiencies in macrophage polarization in aged mice could be restored with exercise and diet changes. 51,55 Diabetes Deficient wound healing is also a severe and potentially fatal consequence of diabetes. The mechanisms by which diabetics suffer from unhealed chronic wounds are multifactorial but do involve dysfunctional macrophage responses. ...
Article
Macrophages are critically involved in wound healing, from dampening inflammation to clearing cell debris and coordinating tissue repair. Within the wound, the complexity of macrophage function is increasingly recognized, with adverse outcomes when macrophages are inappropriately activated, such as in fibrosis or chronic non‐healing wounds. Recent advances in in vivo and translational wound models, macrophage‐specific deletions and new technologies to distinguish macrophage subsets, have uncovered the vast spectrum of macrophage activation and effector functions. Here, we summarize the main players in wound‐healing macrophage activation and function, including cytokines, apoptotic cells, nucleotides and mechanical stimuli. We highlight recent studies demonstrating cooperation between these factors for optimal wound healing. Next, we describe recent technologies such as cell tracking and single‐cell RNA‐seq, which have uncovered remarkable plasticity and heterogeneity in blood‐derived or tissue‐resident macrophages and discuss the implications for wound healing. Lastly, we evaluate macrophage dysfunction in aberrant wound healing that occurs in aging, diabetes and fibrosis. A better understanding of the longevity and plasticity of wound‐healing macrophages, and identification of unique macrophage subsets or specific effector molecules in wound healing, would shed light on the therapeutic potential of manipulating macrophage function for optimal wound healing.
... Exercise and caloric restriction (CR) are two established methods shown to induce autophagy in several tissues [42,[132][133][134][135]. In addition, exercise and CR enhance cellular function of both MuSCs and macrophages [136][137][138][139][140]. The following sections will discuss how autophagy may play a role for each approach. ...
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Skeletal muscle has remarkable regenerative capacity, relying on precise coordination between resident muscle stem cells (satellite cells) and the immune system. The age-related decline in skeletal muscle regenerative capacity contributes to the onset of sarcopenia, prolonged hospitalization, and loss of autonomy. Although several age-sensitive pathways have been identified, further investigation is needed to define targets of cellular dysfunction. Autophagy, a process of cellular catabolism, is emerging as a key regulator of muscle regeneration affecting stem cell, immune cell, and myofiber function. Muscle stem cell senescence is associated with a suppression of autophagy during key phases of the regenerative program. Macrophages, a key immune cell involved in muscle repair, also rely on autophagy to aid in tissue repair. This review will focus on the role of autophagy in various aspects of the regenerative program, including adult skeletal muscle stem cells, monocytes/macrophages, and corresponding age-associated dysfunction. Furthermore, we will highlight rejuvenation strategies that alter autophagy to improve muscle regenerative function.
... The goal of prerehabilitation is to improve the fitness of patients prior to undergoing a major medical intervention, such as cancer surgery [10]. Faster recovery, fewer wound complications, and improved HRQoL have been exhibited by patients who have participated in a prerehabilitation program [11][12][13]. In patients with breast cancer, low levels of physical activity are associated with a 22% higher risk of breast cancer mortality [14]. ...
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Background The positive impact that physical activity has on patients with cancer has been shown in several studies over recent years. However, supervised physical activity programs have several limitations, including costs and availability. Therefore, our study proposes a novel approach for the implementation of a patient-executed, activity tracker–guided exercise program to bridge this gap. Objective Our trial aims to investigate the impact that an activity tracker–guided, patient-executed exercise program for patients undergoing radiotherapy has on cancer-related fatigue, health-related quality of life, and preoperative health status. Methods Patients receiving postoperative radiotherapy for breast cancer (OnkoFit I trial) or neoadjuvant, definitive, or postoperative treatment for other types of solid tumors (OnkoFit II trial) will be randomized (1:1:1) into 3-arm studies. Target accrual is 201 patients in each trial (50 patients per year). After providing informed consent, patients will be randomized into a standard care arm (arm A) or 1 of 2 interventional arms (arms B and C). Patients in arms B and C will wear an activity tracker and record their daily step count in a diary. Patients in arm C will receive personalized weekly targets for their physical activity. No further instructions will be given to patients in arm B. The target daily step goals for patients in arm C will be adjusted weekly and will be increased by 10% of the average daily step count of the past week until they reach a maximum of 6000 steps per day. Patients in arm A will not be provided with an activity tracker. The primary end point of the OnkoFit I trial is cancer-related fatigue at 3 months after the completion of radiotherapy. This will be measured by the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire. For the OnkoFit II trial, the primary end point is the overall quality of life, which will be assessed with the Functional Assessment of Cancer Therapy-General sum score at 6 months after treatment to allow for recovery after possible surgery. In parallel, blood samples from before, during, and after treatment will be collected in order to assess inflammatory markers. Results Recruitment for both trials started on August 1, 2020, and to date, 49 and 12 patients have been included in the OnkoFit I and OnkoFit II trials, respectively. Both trials were approved by the institutional review board prior to their initiation. Conclusions The OnkoFit trials test an innovative, personalized approach for the implementation of an activity tracker–guided training program for patients with cancer during radiotherapy. The program requires only a limited amount of resources. Trial Registration ClinicalTrials.gov NCT04506476; https://clinicaltrials.gov/ct2/show/NCT04506476. ClinicalTrials.gov NCT04517019; https://clinicaltrials.gov/ct2/show/NCT04517019. International Registered Report Identifier (IRRID) DERR1-10.2196/28524
... However, 304 pertaining to the objective of this scoping review, the demonstration that PA-induced improvement in 305 blood perfusion has a direct influence on wound healing parameters is less clear. Results for animal 306 studies tend to support this relationship [64,65] but do not allow for generalization to humans. With that 307 in mind, non-weight-bearing PA aimed at stimulating lower limb perfusion as a mean of improving DFU 308 healing, namely with Buerger exercises, seems beneficial [28,33,36] or at least non-detrimental [34, 35, 309 37]. ...
Article
Background Being physically active on a regular basis has a favorable impact on diabetes-related complications. To the exception of evidence advising individuals with an active diabetic foot ulceration (DFU) to avoid weight-bearing activity, no physical activity (PA) recommendations are currently provided for this population. Objective The aim of this scoping review was to examine and map the existing research evidences of PA participation for individuals with an active DFU. Design A scoping review using Arksey and O’Malley framework was conducted in electronic databases and grey literature from inception to June 2020. Publications that investigated individuals with type 1 or 2 diabetes and an active DFU at enrollment in relation with a PA intervention. Reported outcomes had to inform on effects of PA on any health or wound’s parameters. Results Nineteen articles from 17 distinct studies met inclusion criteria. There are fourteen included studies published in the last 10 years. Types of exercises and materials used, duration of studies, offloading considerations, provision of wound care and varied greatly between studies. Included studies are heterogenous in methodological designs and aims, and reporting was often lacking important components of wound care and PA interventions. A discussion based on descriptive statistics and narrative analysis is provided. Conclusions It is not possible from this scoping review to determine what would be the ideal components of a PA program for this specific population. Conclusions are limited by the quality and designs of the included studies. No articles evaluated quality of life, mortality, or cardiorespiratory capacity, nor were adverse effects routinely reported.
... [3][4][5][6] Furthermore, there is some DFU and non-DFU wound research indicating exercise may aid wound healing. [7][8][9][10] Because of this dilemma, patients with plantar DFUs are commonly recommended to restrict their weight-bearing activity and increase non-weightbearing activity, such as stationary cycling. 1,4,[11][12][13] Recommendations to restrict weight-bearing activity, which for this population mainly concerns walking and standing, are similar to those that were long-held for patients with the most common risk factor for DFU, namely diabetic peripheral neuropathy (DPN). ...
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Physical activity is an essential part of general health and diabetes management. However, recommending weight-bearing physical activity for people with plantar diabetic foot ulcers is controversial, even when gold standard offloading devices are used, as it is commonly thought to delay healing. We aimed to narratively review relevant studies investigating the relationship between plantar diabetic foot ulcer healing and weight-bearing activity, plantar pressure and device adherence. We defined relevant studies as those from two systematic reviews, along with those identified since using a similar updated Pubmed search strategy. We identified six studies. One study found that more daily steps were associated with worse ulcer healing, three found no significant association between steps and ulcer healing, and in two others the association was unclear. Thus, there is weak evidence for an inverse relationship between weight-bearing physical activity and plantar ulcer healing while utilizing offloading devices. We propose a Diabetic foot Offloading and Activity framework to guide future research to find the optimal balance between the positive and negative effects of weight-bearing activity in the context of foot ulcers. We hope such future studies will shed more conclusive light on the impact of weight-bearing activity on healing of plantar diabetic foot ulcers.
... However, several Wistar rats experienced fatigue and then death, so the researchers lowered the MSC and load without reducing the essence of the high-intensity physical exercise. 18,19 Wound healing occurs in the proliferation phase, after haemostasis and inflammation but before remodelling. In the proliferation phase, several vital processes are related to studying the number of fibroblasts and neovascularisation. ...
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Background: Physical exercise has been proven to accelerate wound healing. Physical training itself consists of aerobic (continuous training) and anaerobic (interval training) exercise. The effectiveness of continuous physical exercise on post-tooth extraction wound healing is the focus of this study. Purpose: This study aims to investigate the differences in post-tooth extraction wound healing in Wistar rats (Rattus norvegicus) after aerobic and anaerobic exercise based on the number of fibroblasts and neovascularisation. Methods: Wistar rats were divided into three groups: the control group (K1); K2 undertook continuous aerobic exercise, swimming at 50% maximum swimming capacity (MSC) with an additional 3% bodyweight load; K3 undertook anaerobic continuous exercise, swimming at 65% MSC with a 6% load. The rats swam three times per week for six weeks. The number of fibroblasts and neovascularisation were examined three days after tooth extraction. Data was analysed using the one-way analysis of variance (ANOVA) and Least Significant Difference (LSD) tests (p<0.05). Results: There was a significant difference in the number of fibroblasts between the K2 and K3 groups. There was no significant difference between K2 and K3 in the amount of neovascularisation. Conclusion: There were differences in the number of fibroblasts but not neovascularisation after tooth extraction in Wistar rats given aerobic and anaerobic continuous training.
... Yet, the casualty between exercise and wound healing has not been established. To our knowledge, only a few animal and human studies have investigated the role of exercise on wound healing [80][81][82][83][84] with results indicating that exercise may be able to play a supporting role in wound healing of healthy human adults and for patients with chronic leg wounds 80,81 as long as the adherence rates to exercise are high. 85 Unfortunately, nonadherence to treatment is a widespread problem for patients with DFUs. ...
Article
Abstract Aim. Exercise therapy is a core element in the treatment of diabetes, but the benefits and harms for patients with a diabetic foot ulcer (DFU) are unknown. We therefore aimed to systematically review the benefits on health-related quality of life (HRQoL) and harms of exercise therapy for patients with DFU. Methods. We searched 6 major databases. We performed citation and reference searches of included studies and contacted authors of ongoing trials. We included randomized controlled trials (RCTs) to assess potential benefits on HRQoL and harms of exercise therapy. Observational studies were included to identify potential harms of exercise therapy. Results. We included 10 published publications of 9 trials and results from 2 unpublished trials including a total of 281 individuals with DFUs receiving various forms of exercise therapy. Due to lack of HRQoL measurements and high heterogeneity, it was not possible to perform meta-analyses. Results on HRQoL was present in one unpublished study. Harms reported ranged from musculoskeletal problems, increased wound size, to amputation; however, no safe conclusions could be drawn from the available data due to high heterogeneity and risk of bias in the trials. Conclusions/ Interpretation. Protective strategies are often preferred over therapeutic exercise that might have unforeseen consequences for patients over time. Based on the current literature, no evidence-based recommendations can be provided on the benefits and harms of exercise therapy for patients with DFUs. Well-conducted RCTs are needed to guide rehabilitation including detailed description of adverse events and an exercise program in a semisupervised or fully supervised setting.
... Researchers are slowly coming to a consensus that physical activity produces a U-shaped response curve, with both no and extreme physical activity having deleterious effects, whereas moderate physical activity has beneficial effects on both overall health and immune system function [14]. Moderate intensity exercise has been shown to provide beneficial effects, retarding development of various chronic conditions like cardiovascular disease, atherosclerosis and chronic inflammation and it also reducing the progression of these diseases and certain neoplasms if they are already present [15,16]. The production of greater concentrations of anti-inflammatory cytokines as a result of exercise and this production has been demonstrated and this is essential for the positive effects of exercise [17]. ...
Article
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Polychlorinated biphenyls (PCBs) are environmental pollutants and endocrine disruptors, harmfully affecting reproductive, endocrine, neurological and immunological systems. This broad influence has implications for processes such as wound healing, which is modulated by the immunological response of the body. Conversely, while PCBs can be linked to diminished wound healing, outside of PCB pollution systems, exercise has been shown to accelerate wound healing. However, the potential for moderate intensity exercise to modulate or offset the harmful effects of a toxin like PCB are yet unknown. A key aim of the present study was to examine how PCB exposure at different doses (0, 100, 500, 1000 ppm i.p.) altered wound healing in exercised versus non-exercised subgroups of mice. We examined PCB effects on immune function in more depth by analyzing the concentrations of cytokines, interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), Interleukin-6 (IL-6) and granulocyte macrophage colony stimulating factor (GM-CSF) in these wounds inflicted by punch biopsy. Mice were euthanized at Day 3 or Day 5 after PCB injection (n = 3–6) and skin excised from the wound area was homogenized and analyzed for cytokine content. Results revealed that wound healing was not signficantly impacted by either PCB exposure or exercise, but there were patterns of delays in healing that depended on PCB dose. Changes in cytokines were also observed and depended on PCB dose and exercise experience. For example, IL-1β concentrations in Day 5 mice without PCB administration were 33% less in exercised mice than mice not exercised. However, IL-1β concentrations in Day 3 mice administered 100 ppm were 130% greater in exercised mice than not exercisedmice. Changes in the other measured cytokines varied with mainly depressions at lesser PCB doses and elevations at higher doses. Exercise had diverse effects on cytokine levels, but increased cytokine levels in the two greater doses. Explanations for these diverse effects include the use of young animals with more rapid wound healing rates less affected by toxin exposure, as well as PCB-mediated compensatory effects at specific doses which could actually enhance immune function. Future work should examine these interactions in more detail across a developmental time span. Understanding how manipulating the effects of exposure to environemntal contaminants using behavioral modification could be very useful in certain high risk populations or exposed individuals.
... In a meta-analysis of randomized-controlled surgical trials, Grant et al. found that surgery protocols with reduced length of stay were associated with 0.75 of the risk of SSIs compared to the conventional controls [11]. The level of physical activity has been significantly correlated with the rate of wound healing [10,18], and there is extensive evidence linking either reduced physical activity or expectations of physical activity with hospital stay [1,4,6,7]. This is additionally an important consideration for patients undergoing ACLR who are eager to return to activity. ...
Article
Purpose: To compare the occurrence of short-term postoperative complications between inpatient and outpatient anterior cruciate ligament reconstruction. Methods: The ACS National Surgical Quality Improvement Program (NSQIP) database was utilized to identify patients undergoing arthroscopic anterior cruciate ligament reconstruction (ACLR) from 2007 to 2017. A total of 18,052 patients were available for analysis following application of exclusion criteria. Patients were categorized based on location of surgery. Inpatients and outpatient ACLR groups were matched by demographics and preoperative laboratory values and differences in 30-day complication rates following surgery were assessed. Significance was set with alpha < 0.05. Results: From 2007 to 2017, there was an increasing frequency for outpatient ACLR (p < 0.001), while the incidence of inpatient ACLR remained largely constant (n.s). Groups were matched to include 1818 patients in each cohort. Within the first 30 days of surgery, patients in the inpatient ACLR group experienced significantly greater rates of superficial incisional SSI (0.6% vs 0.1%, p = 0.026) and composite surgical complications (0.6% vs 0.2%, p = 0.019), as well as a greater rate of reoperation (0.7% vs 0.2%, p = 0.029). Inpatient procedures also demonstrated a greater rate of deep surgical incisional SSI (0.2% vs 0.0%, n.s) and readmission to hospital (0.8% vs 0.7%, n.s).Outpatient ACLR procedures were also associated with a significantly greater relative value unit (RVU)/h compared with inpatient ACLRs (0.17 vs 0.14, p < 0.001). Conclusions: Inpatient ACLR may have an increased risk of postoperative complications compared to outpatient ACLR during the short-term postoperative period. Although some patients may require admission post-operatively for medical and/or pain management, doing so is not necessarily without a degree of risk. Level of evidence: III
... 7 Exercise physiologists also have discovered the ability of physical exercise in accelerating wound healing in mice and humans. 8 Furthermore, continuous physical exercise with moderate intensity showed an increase in the number of fibroblasts and the amount of neovascularization in Wistar rats (Rattus norvegicus) after tooth extraction which results in acceleration of wound healing. 9 In addition, there are also studies that have proven that there is an increase in vascular endothelial growth factors (VEGF) which triggers an increase in tissue neovascularization in the wound healing process after tooth extraction in Wistar rats (Rattus norvegicus) that perform moderate intensity physical exercise. ...
Article
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Introduction. The healing process of tooth extraction is desired to take place faster to restore the normal tissue. Physical exercise is proven to accelerate wound healing through various physiological mechanisms. Aerobic exercise increases oxygen perfusion which leads to wound healing process. On the other hand, anaerobic exercise stimulates reactive oxygen species and may interfere with the wound healing process.
... Exercise has been shown to increase natural killer cell cytotoxicity, monocyte and macrophage number and function and the CD8 T-cell ratio. Furthermore, it has been shown to decrease the increased antigen presentation, inflammation and number of proinflammatory monocytes and prevent the accumulation of aged T-cells [121][122][123] . These mechanisms demonstrate the complexity of interaction between the risk of cancer and physical activity. ...
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In recent years, because of improved cancer screening, detection and treatment modalities, a rapid increase in the population of colorectal and other cancer survivors has been observed. The increasing population has justified the requirement of preventive strategies such as lifestyle modifications with regard to obesity, physical activity, diet and smoking. Physical activity may prevent approximately 15% of the colon cancers. Furthermore, several observational studies have demonstrated the efficacy and dose-dependent and anti-cancer effects of exercise on decreasing the mortality and risk of recurrence before and after the colorectal cancer (CRC) diagnosis. However, the required exercise dose, type and intensity are yet unclear. The results of randomised prospective studies are expected to determine the optimal amount, type and intensity of exercise and formulate the most appropriate exercise plan and guidelines, according to the requirements and comorbidities of the patients. In addition, recent studies have focused on the molecular and genetic mechanisms underlying the effect of physical activity on disease outcomes and recurrence rates. This review aimed to investigate the effects of physical activity and the biological basis of these effects in preventing the risk and recurrence of CRC and decreasing the hazards of cancer and cancer treatment. Key Words: Colorectal cancer, Exercise, Physical activity
... Nonetheless, long-term exercise-based protocols in mice have shown to promote improved immune function. With regard to macrophages, these effects can be associated with increased phagocytic activity (Sugiura et al. 2001) or accelerated phenotype switching that leads to quicker wound healing (Goh and Ladiges 2014;Pence and Woods 2014). For the lymphocytes, long-term exercise seems to promote increased turnover of these cells by stimulation of cell proliferation ) and apoptosis (Kr€ uger and Mooren 2014). ...
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Although previous studies have shown that forced exercise modulates inflammation and is therapeutic acutely for experimental autoimmune encephalomyelitis (EAE), the long-term benefits have not been evaluated. In this study, we investigated the effects of preconditioning exercise on the clinical and pathological progression of EAE. Female C57BL/6 mice were randomly assigned to either an exercised (Ex) or unexercised (UEx) group and all of them were induced for EAE. Mice in the Ex group had an attenuated clinical score relative to UEx mice throughout the study. At 42 dpi, flow cytometry analysis showed a significant reduction of B-cells, CD4(+) T-cells and CD8(+) T-cells infiltrating into the spinal cord in the Ex group compared to UEx. Ex mice also had a significant reduction in myelin damage with a corresponding increase in proteolipid protein expression. Finally, Ex mice had a significant reduction in axonal damage. Collectively, our study demonstrates for the first time that a prolonged and forced preconditioning protocol of exercise improves clinical outcome and attenuates pathological hallmarks of EAE at chronic disease. This article is protected by copyright. All rights reserved.
Chapter
As the skin ages, the normal signs of aging such as alterations in pigmentation and increased wrinkling become more obvious. Although these changes appear to be mainly cosmetic, under the epidermis there is a gradual change in resident cell populations and loss of function. These changes result in a decreased ability to regulate homeostasis and underlie the delay in skin healing that occurs with age. Changes in hemostasis cause blood clotting to occur slowly and influence the healing progression. Likewise, age-related inflammatory changes in wounds most influence the latter phases of repair, including cellular proliferation and remodeling. Alterations in the stem cell populations that provide new cells to the healing wound occur, since this vital cell population is diminished in aged individuals. Thus, when a wound occurs, the normal stages of wound healing will proceed, although at an altered rate. In unfavorable conditions, this can result in an increased likelihood of infection or ulcer formation. Additionally, diseases associated with aging such as diabetes and vascular disease can amplify the alterations in wound healing, increasing the likelihood of wound complications. As research in the aged skin continues, the changes in the skin that affect wounding will continue to be elucidated, giving rise to new treatments for this growing patient population.
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Significance: With the growing population of baby boomers, there is a great need to determine the effects of advanced age on the function of the immune system. Recent Advances: It is universally accepted that advanced age is associated with a chronic low-grade inflammatory state referred to as inflamm-aging which alters the function of both immune and non-immune cells. Mononuclear phagocytes play a central role in both the initiation and resolution of inflammation in multiple organ systems and exhibit marked changes in phenotype and function in response to environmental cues, including the low levels of pro-inflammatory mediators seen in the aged. Critical Issues: While we know a great deal about the function of immune cells in young adults and there is a growing body of literature focusing on aging of the adaptive immune system, much less is known about the impact of age on innate immunity and the critical role of the mononuclear phagocytes in this process. Future Directions: In this review, there is a focus on the tissue-specific monocyte and macrophage subsets and how they are altered in the aged milieu with the hope that this compilation of observations will spark an expansion of research in the field.
Conference Paper
Exercise is complementary to cancer prevention, care, and survivorship. Exercise is considered safe and effective during and after cancer treatment when conducted under supervision and in controlled environments. Less is known about the safety and effectiveness of unsupervised, home-based exercise programs. Implementing methods of monitoring and reporting can provide more information and potentially enhance exercise effects and program integrity. This paper describes the development of REMEDY, a remote monitoring sensor system consisting of a wireless body-area network (WBAN), cloud database, mobile assisted application, and a set of intelligent algorithms. REMEDY can provide real-time exercise monitoring, participant feedback, and quality assessment that may lead to safer and more effective exercise programs and exercises for cancer patients and survivors.
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Cardiac aging is characterized by myocardial hypertrophy, fibrosis, and diastolic dysfunction. Human kallikrein (hKLK1) protects against fibrosis in various pathogenic states. However, the effects of hKLK1 overexpression on cardiac aging-related fibrosis and the underlying mechanisms remain unknown. Moreover, the role of hKLK1 in regulating macrophage function leading to cardiac fibrosis has not been investigated. Thus, in this study, we determined the effects of hKLK1 on cardiac aging and explored the mechanisms through which hKLK1 regulated aging-related fibrosis. Echocardiographic measurements showed that aging caused significant alternations in cardiac morphology, hypertrophy, and fibrosis in rats, and hKLK1 overexpression protected against aging-induced cardiac dysfunction. Compared with wild-type hearts, the hKLK1 transgene decreased the expression of monocyte chemoattractant protein 1 and suppressed mitochondrial dysfunction and excess oxidative stress, leading to decreased recruitment and retention of alternatively activated (M2) macrophages and reduced secretion of profibrotic cytokines mediated by the TGF-β1-Smad3 signaling pathway in hearts of aging rats. Furthermore, these cardioprotective effects of hKLK1 overexpression were associated with the Janus kinase-signal transducer and activator of transcription 3 signaling pathway. H2O2-induced senescence promoted the differentiation of RAW264.7 cells into M2-type cells induced by IL-4 treatment. Bradykinin treatment relieved the migratory capacity of macrophages induced by H2O2. Thus, hKLK1 overexpression reduced cardiac fibrosis and improved aging-related cardiac dysfunction through reduced shift of macrophages to M2 macrophages, indicating that hKLK1 may alleviate aging-related cardiac dysfunction.-Hu, D., Dong, R., Yang, Y., Chen, Z., Tang, Y., Fu, M., Wang, D. W., Xu, X., Tu, L. Human kallikrein overexpression alleviates cardiac aging by alternatively regulating macrophage polarization in aged rats.
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Background: Resistance exercise is beneficial for the immune system, including decreased susceptibility to infections and improved effectiveness of vaccinations. This review aims to provide a systematic analysis of the literature regarding the impact of resistance exercise on immune cells in the blood circulation. Materials and methods: The protocol of this review followed the PRISMA guidelines and registered in PROSPERO (ID: CRD42020157834). PubMed and Web-of-Science were systematically searched for relevant articles. Outcomes were divided into two categories: 1) inflammatory gene expression or secretion of inflammation-related cytokines and 2) other aspects such as cell migration, proliferation, apoptosis, phagocytosis, and redox status. Results: Thirty intervention studies were included in this review, of which 11 articles were randomized controlled trials and six non-randomized controlled trials. Although only resistance exercise interventions were included, there was a high heterogeneity regarding specific exercise modalities. The most frequently studied outcome measures were the gene and protein expression levels in peripheral blood mononuclear cells (PBMC). This review reveals that already one acute exercise bout activates the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway in PBMC. Although resistance exercise induces an acute cytosolic oxidative stress response, the antioxidant enzyme expression is improved after resistance training period. Natural killer cell activity increases in older but decreases in younger adults immediately after a resistance exercise bout. Moreover, resistance exercise improves neutrophil phagocytic activity. Finally, effects on lymphocyte proliferation remain unclear. Conclusions: The results of this systematic review demonstrate that resistance exercise has beneficial effects on several aspects of immune cell function both in young and older individuals. Acute changes in immune cell function occur already after a single bout of resistance exercise. However, regular resistance training during several weeks seems necessary to obtain beneficial adaptations that can be related to better immunity and reduced inflammation. The effects documented in this review confirm the beneficial effects of resistance exercise in young as well as older persons on the immune cell function.
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The prevalence of obesity, an established epidemiological risk factor for many cancers, has risen steadily for the past several decades in the US and many other countries. Particularly alarming are the increasing rates of obesity among children, portending continuing increases in the rates of obesity and obesity-related cancers for many years to come. Modulation of energy balance, via increased physical activity, has been shown in numerous comprehensive epidemiological reviews to reduce cancer risk. Unfortunately, the effects and mechanistic targets of physical activity interventions on the carcinogenesis process have not been thoroughly characterized. Studies to date suggest that exercise can exert its cancer-preventive effects at many stages during the process of carcinogenesis, including both tumour initiation and progression. As discussed in this review, exercise may be altering tumour initiation events by modifying carcinogen activation, specifically by enhancing the cytochrome P450 system and by enhancing selective enzymes in the carcinogen detoxification pathway, including, but not limited to, glutathione-S-transferases. Furthermore, exercise may reduce oxidative damage by increasing a variety of anti-oxidant enzymes, enhancing DNA repair systems and improving intracellular protein repair systems. In addition to altering processes related to tumour initiation, exercise may also exert a cancer-preventive effect by dampening the processes involved in the promotion and progression stages of carcinogenesis, including scavenging reactive oxygen species (ROS); altering cell proliferation, apoptosis and differentiation; decreasing inflammation; enhancing immune function; and suppressing angiogenesis. A paucity of data exists as to whether exercise may be working as an anti-promotion strategy via altering ROS in initiated or preneoplastic models; therefore, no conclusions can be made about this possible mechanism. The studies directly examining cell proliferation and apoptosis have shown that exercise can enhance both processes, which is difficult to interpret in the context of carcinogenesis. Studies examining the relationship between exercise and chronic inflammation suggest that exercise may reduce pro-inflammatory mediators and reduce the state of low-grade, chronic inflammation. Additionally, exercise has been shown to enhance components of the innate immune response (i.e. macrophage and natural killer cell function). Finally, only a limited number of studies have explored the relationship between exercise and angiogenesis; therefore, no conclusions can be made currently about the role of exercise in the angiogenesis process as it relates to tumour progression. In summary, exercise can alter biological processes that contribute to both antiinitiation and anti-progression events in the carcinogenesis process. However, more sophisticated, detailed studies are needed to examine each of the potential mechanisms contributing to an exercise-induced decrease in carcinogenesis in order to determine the minimum dose, duration and frequency of exercise needed to yield significant cancer-preventive effects, and whether exercise can be used prescriptively to reverse the obesity-induced physiological changes that increase cancer risk.
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The limited amount of information on the primary age-related deficiencies in the innate immune system led us to study the production of inducible nitric oxide synthase (iNOS), arginase, and cytokines in macrophages of young (8 weeks old) and old (72 weeks old) female BALB/c mice. We first evaluated iNOS and arginase inducers on peritoneal (PM phi) and bone marrow-derived (BMM phi) macrophages of young BALB/c and C57BL/6 mice, and then investigated their effects on macrophages of old mice. Upon stimulation with lipopolysaccharide (LPS), resident and thioglycolate-elicited PM phi from young mice presented higher iNOS activity than those from old mice (54.4%). However, LPS-stimulated BMM phi from old mice showed the highest NO levels (50.1%). Identical NO levels were produced by PM phi and BMM phi of both young and old mice stimulated with interferon-gamma. Arginase activity was higher in resident and elicited PM phi of young mice stimulated with LPS (48.8 and 32.7%, respectively) and in resident PM phi stimulated with interleukin (IL)-4 (64%). BMM phi of old mice, however, showed higher arginase activity after treatment with IL-4 (46.5%). In response to LPS, PM phi from old mice showed the highest levels of IL-1 alpha (772.3 +/- 51.9 pg/mL), whereas those from young mice produced the highest amounts of tumor necrosis factor (TNF)-alpha (937.2 +/- 132.1 pg/mL). Only TNF-alpha was expressed in LPS-treated BMM phi, and cells from old mice showed the highest levels of this cytokine (994.1 +/- 49.42 pg/mL). Overall, these results suggest that macrophages from young and old mice respond differently to inflammatory stimuli, depending on the source and maturity of the cell donors.
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Epidemiological research suggests that regular physical activity confers beneficial effects that mediate an anti-tumor response and may reduce cancer recurrence. It is unclear what amount of physical activity is necessary to exert such a protective effect and what mechanisms are involved. We investigated the effects of voluntary wheel running on tumor progression and cytokine gene expression in the transgenic polyoma middle T oncoprotein (PyMT) mouse model of invasive breast cancer. Runners showed significantly reduced tumor sizes compared with non-runners after 3 weeks of running (p≤0.01), and the greater the running distance the smaller the tumor size (Pearson's r = -0.61, p≤0.04, R(2) = 0.38). Mice running greater than 150 km per week had a significantly attenuated tumor size compared with non-runners (p≤0.05). Adipose tissue mass was inversely correlated with tumor size in runners (Pearson's r = -0.77, p = 0.014) but not non-runners. Gene expression of CCL22, a cytokine associated with recruitment of immunosuppressive T regulatory cells, was decreased in tumors of runners compared to non-runners (p≤0.005). No differences in tumor burden or metastatic burden were observed between runners and non-runners after ten weeks of running when the study was completed. We conclude that voluntary wheel running in PyMT mice correlates with an attenuation in tumor progression early during the course of invasive breast cancer. This effect is absent in the later stages of overwhelming tumor burden even though cytokine signaling for immunosuppressive regulatory T cells was down regulated. These observations suggest that the initiation of moderate exercise training for adjunctive therapeutic benefit early in the course of invasive breast cancer should be considered for further investigation.
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Obese individuals are characterized by low circulating adiponectin concentrations and an increased number of macrophages in adipose tissue, which is believed to be causally associated with chronic low-grade inflammation and insulin resistance. Regular physical exercise decreases overall morbidity in obese subjects which may be due to modulations of inflammatory pathways. In this randomized clinical trial we investigated the separate effects of endurance training-induced weight loss, diet-induced weight loss and endurance training per se (without weight loss) on plasma adiponectin multimer composition (Western blotting) and adipose tissue macrophage content (immunohistochemistry) in young, moderately overweight men. Weight loss and endurance training per se decreased whole body fat percentage in an additive manner. No intervention-induced changes were observed for plasma total adiponectin. Surprisingly, endurance training, irrespectively of any associated weight loss, shifted the adiponectin multimer distribution towards a lower molecular weight (21% decrease in HMW/LMW, P=0.015) whereas diet-induced weight loss shifted the distribution towards a higher molecular weight (42% increase in HMW/MMW, P<0.001). Furthermore, endurance training per se increased the number of anti-inflammatory CD163(+) macrophages (from 12.7 [2.1] (mean [SE]) to 16.1 [3.1] CD163(+) cells/100 adipocytes, P=0.013), whereas diet-induced weight loss tended to decrease CD68(+) macrophages in subcutaneous abdominal adipose tissue. Thus, regular physical exercise influences systemic and adipose tissue inflammatory pathways differently than diet-induced weight loss in younger, moderately overweight men. Our data suggest that some of the health benefits of a physically active lifestyle may occur through modulations of anti- rather than pro-inflammatory pathways in young, overweight men.
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Physical exercise can improve health and may lead to changes in the functionality of the immune system. Moderate intensity exercise can reduce the risk of infection by shifting the overall immune response towards a T helper type 1 pattern. This study investigates the effect of 12 weeks of swimming on the cytokine profile of lymph node cells and macrophages and of the nitric oxide production by these cells. BALB/c mice were divided into 2 groups. The exercise group was subjected to swimming exercise. Lymph node cells culture showed that concentrations of interferon-γ and tumour necrosis factor-α were higher in the exercised group, while levels of interleukine-4 and interleukine-10 were significantly decreased in this group. The interleukine-10/interferon-γ ratio tended towards a T helper type 1 profile. Moreover, macrophages isolated from exercised mice produced more interleukine-12 and tumour necrosis factor-α following lipopolysaccharide stimulus. Challenging these macrophages with Leishmania major resulted in higher interleukine-12 production than was observed with macrophages from the control group. Nitric oxide production was increased in macrophages isolated from exercised group following lipopolysaccharide stimulus but not following infection with Leishmania major. These data suggest that exercise biases the immune system towards a T helper type 1 response profile.
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This study aims to investigate cytokine synthesis by lymphocytes in the presence of mammary tumors and the interaction with physical activity. For this study, we used 56 female Balb/c, 8-week-old, virgin mice with a body mass between 20 and 30 g. The mice were divided into four groups: a no tumor/nontrained control group; a no tumor/trained group subjected to physical training of swimming in water (30±4°C) for 45 min, five times per week for 8 weeks; a tumor/nontrained (sedentary) group in which the animals received 7,12-dimethylbenzanthracene [(DMBA) 1 mg/ml weekly for 6 weeks)]; and a tumor/trained group in which animals were subjected to the aforementioned DMBA tumor induction and swim training protocols. After the experimental period, immune cells were collected from spleen cell specimens, placed in culture, and stimulated with lipopolysaccharide. The presence of cluster of differentiation (CD)3, CD4, and CD8 markers and the expression of interferon-γ, interleukin (IL)-2, IL-4, IL-10, IL-12, transforming growth factor β, and tumor necrosis factor α cytokines were assessed by flow cytometry and enzyme-linked immunosorbent assay. Physical activity increased the quantities of lymphocytes producing interferon γ, IL-2, IL-12, and tumor necrosis factor α and decreased the quantities of lymphocytes and macrophages expressing IL-4, IL-10, and transforming growth factor β. In contrast, tumor induction, in the absence of swim training, reduced Th1 cytokine levels while increasing the presence of Th2 cytokines and Treg cells. Physical activity promoted reductions in the incidence of tumor development and promoted immune system polarization toward an antitumor Th1 response pattern profile.
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Macrophages are part of the tumor microenvironment and have been associated with poor prognosis in uveal melanoma. We determined the presence of macrophages and their differentiation status in a murine intraocular melanoma model. Inoculation of B16F10 cells into the anterior chamber of the eye resulted in rapid tumor outgrowth. Strikingly, in aged mice, tumor progression depended on the presence of macrophages, as local depletion of these cells prevented tumor outgrowth, indicating that macrophages in old mice had a strong tumor-promoting role. Immunohistochemistry and gene expression analysis revealed that macrophages carried M2-type characteristics, as shown by CD163 and peroxisome proliferator-activated receptor gamma expression, and that multiple angiogenic genes were heavily overrepresented in tumors of old mice. The M2-type macrophages were also shown to have immunosuppressive features. We conclude that tumor-associated macrophages are directly involved in tumor outgrowth of intraocular melanoma and that macrophages in aged mice have a predisposition for an M2-type profile.
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Cellular senescence suppresses cancer by stably arresting the proliferation of damaged cells. Paradoxically, senescent cells also secrete factors that alter tissue microenvironments. The pathways regulating this secretion are unknown. We show that damaged human cells develop persistent chromatin lesions bearing hallmarks of DNA double-strand breaks (DSBs), which initiate increased secretion of inflammatory cytokines such as interleukin-6 (IL-6). Cytokine secretion occurred only after establishment of persistent DNA damage signalling, usually associated with senescence, not after transient DNA damage responses (DDRs). Initiation and maintenance of this cytokine response required the DDR proteins ATM, NBS1 and CHK2, but not the cell-cycle arrest enforcers p53 and pRb. ATM was also essential for IL-6 secretion during oncogene-induced senescence and by damaged cells that bypass senescence. Furthermore, DDR activity and IL-6 were elevated in human cancers, and ATM-depletion suppressed the ability of senescent cells to stimulate IL-6-dependent cancer cell invasiveness. Thus, in addition to orchestrating cell-cycle checkpoints and DNA repair, a new and important role of the DDR is to allow damaged cells to communicate their compromised state to the surrounding tissue.
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Here, we investigated the effect of jump exercise on tumor growth, cancer cachexia, lymphocyte proliferation and macrophage function in Walker 256 tumor-bearing rats. Male Wistar rats (60 days) were divided into sedentary (C) and exercised (E) groups. Jump training consisted of six sets of 10 jumps in water with overload of 50% of body mass with 1 min of resting, four times per week for 8 weeks. After 6 weeks of training, half of each group was inoculated with 2 x 10(7) cells of Walker 256 tumor. Sedentary tumor-bearing and exercised tumor-bearing are referred to as T and TE, respectively. Tumor weight in the T group was 25 g. These animals display loss of weight, hypertriacylglycerolemia, hyperlacticidemia, depletion of glycogen stores and increase in PIF expression. Jump exercise (TE) induced a significant lower tumor weight, preserves liver glycogen stores, partly prevented the hypertriacylglycerolemia, hyperlacticidemia and, prevented the fall in body weight and reduced PIF expression. Lymphocyte was increased by tumor burden (T) and was higher by including exercise (TE). The same was observed regarding phagocytosis and lysosomal volume. Anaerobic exercise decreases tumor growth, cancer cachexia and increases innate and adaptative immune function.
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Exercise training or higher levels of physical activity are known to exert anti-inflammatory effects. CD14+CD16+ monocytes are potent producers of inflammatory proteins, and elevated levels of these "inflammatory" monocytes have been implicated in disease development. Little is known about the influence of exercise training on this cell population. On the basis of their physical activity pattern, male and female subjects, 65-80 years old, were assigned to a physically active (PA; n=15) or inactive (PI; n=15) group. The PI group performed 12 weeks (3 days/week) of endurance (20 min at 70-80% heart-rate reserve) and resistance exercise training (eight exercises, two sets at 70-80% of one repetition maximum). Subjects in the PA group maintained their habitual activity level. Flow cytometry was used to determine monocyte phenotype and monocyte TLR4 expression. ELISAs were used to measure whole blood, LPS-stimulated TNF-alpha production, and serum C-reactive protein (CRP). At baseline, the PA group had a lower percentage of CD14+CD16+ monocytes and lower unstimulated production of TNF-alpha than the PI group. CD14+CD16+ monocyte percentage and 1 ng/ml LPS-stimulated TNF-alpha production were reduced after the PI group underwent 12 weeks of exercise training. PI subjects also had higher TLR4 expression on classical monocytes, but there were no significant exercise training-induced changes in monocyte TLR4 expression. The PA group had significantly lower serum CRP than the PI group. Physical activity was associated with lower CD14+CD16+ monocyte percentage and LPS-stimulated TNF-alpha production. Exercise training-induced reductions in CD14+CD16+ monocytes may contribute to the anti-inflammatory effects of exercise training.
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Immune function decreases with age, rendering the elderly more susceptible to infection and tumor development. In addition, intense exercise has been shown to decrease immune function in some populations. Few studies have examined the effects of exercise on immune function in the elderly and, to our knowledge, no studies have examined the effects of exercise on a population of active, but nonexercising elderly. The purpose of this study was to examine the effects of a 10-week endurance training program on selected parameters of immune function in active elderly women. A total of 29 healthy, active women, aged 70-87, were randomly assigned to either an exercise (76 +/- 5 years, n = 15) or control (77 +/- 6 years, n = 14) group. The exercise group walked 3 days/week at 70% heart rate reserve (HRR). The duration on day 1 was 20 min and it was increased by 5 min each day until subjects were walking for 50 min (week 3). It remained at 50 min for the duration of the study, while controls maintained normal activity. Blood samples were obtained from both groups at rest, and from the exercise group after 20 min of walking at 70% HRR and after 2 h of recovery. Blood samples were collected prior to endurance training and again after 10 weeks of endurance training. There was a significant decrease in 1-mile walk times as well as heart rate at completion of the walk in the exercise group. Natural cell-mediated cytotoxicity (NCMC) was significantly higher post-exercise, compared to pre-exercise both before and after training. After training it remained significantly elevated 2 h post-exercise. The resting NCMC was significantly decreased in controls at week 10 but not in the exercise group. Ten weeks of endurance training resulted in a significant decrease in both the 1-mile walk time and the post-walk heart rate in the exercisers but not the controls, without resulting in either an acute or chronic suppression of immune function. Further, endurance training may lead to an attenuation of the decrease in cellular immune measures which occurs during the winter, since the control group experienced a decrease in NCMC and the exercisers did not.
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Mammalian cells can respond to damage or stress by entering a state of arrested growth and altered function termed cellular senescence. Several lines of evidence suggest that the senescence response suppresses tumorigenesis. Cellular senescence is also thought to contribute to aging, but the mechanism is not well understood. We show that senescent human fibroblasts stimulate premalignant and malignant, but not normal, epithelial cells to proliferate in culture and form tumors in mice. In culture, the growth stimulation was evident when senescent cells comprised only 10% of the fibroblast population and was equally robust whether senescence was induced by replicative exhaustion, oncogenic RAS, p14(ARF), or hydrogen peroxide. Moreover, it was due at least in part to soluble and insoluble factors secreted by senescent cells. In mice, senescent, much more than presenescent, fibroblasts caused premalignant and malignant epithelial cells to form tumors. Our findings suggest that, although cellular senescence suppresses tumorigenesis early in life, it may promote cancer in aged organisms, suggesting it is an example of evolutionary antagonistic pleiotropy.
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In this study, we determined the effects of age and chronic treadmill running (16 wk; 5 days/wk; 45 min/day; 18-22 m/min) on resident peritoneal macrophage responsiveness to interferon-γ (IFN-γ) and lipopolysaccharide (LPS) in young (6 mo) and aged (22 mo) male BALB/cByJ mice by measuring cytolytic ability and production of reactive nitrogen products. Macrophages (>90% Mac-3+) were incubated with various concentrations of IFN-γ and LPS for 24 h. After washing, P815 tumor cells were utilized as targets in a 16-h51Cr release assay. We found that aging resulted in a significant reduction in the ability of macrophages to respond to the highest doses of IFN-γ and LPS and kill P815 cells (46 ± 4 vs. 34 ± 2% in young and old mice, respectively). Exercise training significantly increased macrophage cytolysis in both age groups (66 + 7 vs. 44 + 2% in young and old mice, respectively); this effect was larger in the young mice. Macrophages from young exercised mice also produced significantly (50-60%) more[Formula: see text]; there was a tendency for higher[Formula: see text] in old exercisers. The inducible nitric oxide synthase (iNOS) inhibitor NG-monomethyl-l-arginine (l-NMMA) significantly reduced macrophage cytolysis and [Formula: see text]production and completely abrogated exercise-induced increases in these measures. RT-PCR analysis revealed significantly higher iNOS mRNA levels in macrophages obtained from the exercise-trained mice and significantly lower iNOS mRNA in old compared with young mice. We conclude that aging reduces and exercise training increases the capacity of resident peritoneal macrophages to respond to IFN-γ and LPS with increased tumor cytolysis. Enhanced iNOS gene expression and[Formula: see text] production are likely the contributing mechanisms of the exercise-induced enhancement of cytolysis in young mice. Whilel-NMMA did block the exercise-induced increase in cytolysis, exercise did not increase[Formula: see text] or iNOS gene expression in the old mice, indicating perhaps the contribution of other cytolytic mechanisms in old mice.
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For most species, aging promotes a host of degenerative pathologies that are characterized by debilitating losses of tissue or cellular function. However, especially among vertebrates, aging also promotes hyperplastic pathologies, the most deadly of which is cancer. In contrast to the loss of function that characterizes degenerating cells and tissues, malignant (cancerous) cells must acquire new (albeit aberrant) functions that allow them to develop into a lethal tumor. This review discusses the idea that, despite seemingly opposite characteristics, the degenerative and hyperplastic pathologies of aging are at least partly linked by a common biological phenomenon: a cellular stress response known as cellular senescence. The senescence response is widely recognized as a potent tumor suppressive mechanism. However, recent evidence strengthens the idea that it also drives both degenerative and hyperplastic pathologies, most likely by promoting chronic inflammation. Thus, the senescence response may be the result of antagonistically pleiotropic gene action. Expected final online publication date for the Annual Review of Physiology Volume 75 is February 10, 2013. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
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Objective: It has become clear that exercise may be a useful therapy in the insulin resistance treatment, as it has anti-inflammatory effects and improves insulin sensitivity. However, it remains uncertain whether exercise affects the adipocytes or infiltrated macrophages. Thus, the aim was to investigate the effects of acute exercise on the inflammatory status and insulin signaling of the white adipose tissue (WAT) fractions (stromal-vascular fraction [SVF] and adipocytes). Design and methods: The effect of acute swimming exercise was investigated on insulin sensitivity, insulin signaling, inflammatory pathways in the WAT fractions of high-fat fed Wistar rats. Additionally, macrophage infiltration and polarization were analyzed in the WAT. Results: Acute exercise can improve insulin signaling in WAT fractions, along with a phenotypic switch from M1- to M2-macrophages in obese rats, as indicated by a marked increase in macrophage galactose-type C-type lectin 1-positive cells in WAT was observed. Additionally, exercise promoted a reduction in circulating levels of lipopolysaccharide, and toll-like receptor 4 activity along with TNF-alpha, IL-1-beta and MCP-1 mRNA levels in WAT fractions. Conclusions: These data suggest that acute exercise improves insulin signaling in the WAT, at least in part by inducing macrophage polarization toward the M2-state.
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Tumor-associated macrophages (TAMs) are key components of the tumor macroenvironment. Cancer- and host cell-derived signals generally drive the functions of TAMs towards an M2-like polarized, tumor-propelling mode; however, when appropriately re-educated. TAMs also have the potential to elicit tumor destructive reactions. Here, we discuss recent advances regarding the immunobiology of TAMs and highlight open questions including the mechanisms of their accumulation (recruitment versus proliferation), their diversity and how to best therapeutically target these cells.
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Over the past decade, modern genetic tools have permitted scientists to study the function of myeloid lineage cells, including macrophages, as never before. Macrophages were first detected more than a century ago as cells that ingested bacteria and other microbes, but it is now known that their functional roles are far more numerous. In this review, we focus on the prevailing functions of macrophages beyond their role in innate immunity. We highlight examples of macrophages acting as regulators of development, tissue homoeostasis, remodeling (the reorganization or renovation of existing tissues) and repair. We also detail how modern genetic tools have facilitated new insights into these mysterious cells.
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The vascular endothelium plays a key role in arterial wall homeostasis by preventing atherosclerotic plaque formation. A primary causal factor of endothelial dysfunction is the reactive oxygen species. Aerobic exercise is ascribed as an important adjuvant therapy in endothelium-dependent cardiovascular disease. However, little is known about the effects of concurrent (aerobic + strength) training on that. For a comparison of the effects of aerobic and concurrent physical training on endothelial function, oxidative stress parameters and the immunoinflammatory activity of monocytes/macrophages, 20 adult male volunteers of middle age were divided into a concurrent training (CT) programme group and an aerobic training group. The glutathione disulphide to glutathione ratio (GSSG/GSH) and plasma lipoperoxide (LPO) levels, as well as flow-mediated dilation (FMD), monocyte/macrophage functional activity (zymosan phagocytosis), body lipid profiles, aerobic capacity (maximal oxygen uptake) and strength parameters (one-repetition maximum test), were measured before and after the exercise training programmes. The CT exhibited reduced acute effects of exercise on the GSSG/GSH ratio, plasma LPO levels and zymosan phagocytosis. The CT also displayed improved lipid profiles, glycaemic control, maximal oxygen uptake and one-repetition maximum test values. In both the aerobic training and the CT, training improved the acute responses to exercise, as inferred from a decrease in the GSSG/GSH ratios. The aerobic sessions did not alter basal levels of plasma LPO or macrophage phagocytic activity but improved FMD values as well as lipid profiles and glycaemic control. In summary, both training programmes improve systemic redox status and antioxidant defences. However, the aerobic training was more efficient in improving FMD in the individuals studied.
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The present investigation was carried out to study the effect of aging on the activation of murine peritoneal macrophages by lipopolysaccharide (LPS) plus interferon-gamma (IFN-gamma) to tumoricidal state. Age-dependent alteration in macrophage-mediated tumor cell binding, cytotoxicity, cytostasis and production of the tumoricidal effector molecules oncostatin M, tumor necrosis factor and nitric oxide (NO) was studied. Macrophages (1.5 x 10(5)) obtained from mice of different age groups were separated on the basis of the reproductive status of the mice into prereproductive (young), reproductive (adult) and postreproductive (old) for studying their activation. Macrophages obtained from the old mice were found to be least responsive to the activation signal of LPS + IFN-gamma for macrophage-mediated tumoricidal activity and production of effector molecules. The macrophages of the old mice did not express inducible nitric oxide synthase, an enzyme responsible for the production of NO by activated macrophages. Macrophages of the adult and young groups showed better response; however, optimal response was observed in the macrophages of adult mice. The reasons for the observed difference in the response of macrophages are discussed.
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The purpose of this study was to examine the effects of exercise training on age-related impairment of immune parameters related to T-cell activation in elderly individuals. Twenty-four elderly subjects were assigned to an exercise training group (EXC: 3 men, 9 women; age 61-76 years) or a nonexercise control group (CON: 4 men, 8 women; age 62-79 years). Subjects in EXC participated in exercise sessions 2 d·wk(-1) for 12 weeks. The training session included stretching and endurance exercise (10 minutes), resistance training comprised leg extension, leg press, hip abduction, and hip adduction using exercise machine and each subject's body weight. Subjects in CON maintained their normal physical activity levels during the study period. Blood samples were collected before and after the training period. Samples were measured for the numbers of leukocytes, lymphocytes, and monocytes, and for CD3(+), CD4(+), CD8(+), CD28(+)CD4(+), CD28(+)CD8(+), TRL-4(+)CD14(+), and CD80(+)CD14(+) cells. The number of leukocytes, lymphocytes, monocytes, CD3(+), CD4(+), and CD8(+) cells did not change after 12 weeks in either EXC or CON. The number of CD28(+)CD8(+) cells increased significantly after training in EXC (p ≤ 0.05), although CON showed no significant change. In the EXC group, CD80(+)CD14(+) cell counts were significantly higher after training (p ≤ 0.05), but the TLR-4(+)CD14(+) cell counts were unchanged. In the CON group, no significant alteration existed in TLR-4(+)CD14(+) and CD80(+)CD14(+) cell numbers. In conclusion, exercise training in elderly people is associated with increased CD28-expressing Tc cells and CD80-expressing monocytes. Therefore, exercise training might upregulate monocyte and T-cell-mediated immunity in elderly people.
Article
The phenotype of wound macrophages has not been studied by direct examination of these cells, yet macrophages recruited to sites of injury are described as alternatively activated macrophages, requiring IL-4 or IL-13 for phenotypic expression. This study characterized wound macrophage phenotype in the PVA sponge wound model in mice. Eighty-five percent of wound macrophages isolated 1 day after injury expressed Gr-1, but only 20% of those isolated at 7 days expressed this antigen. Macrophages from 1-, 3-, and 7-day wounds expressed markers of alternative activation,including mannose receptor, dectin-1, arginase 1,and Ym1, but did not contain iNOS. Day 1 wound macrophages produced more TNF-alpha, more IL-6, and less TGF-beta than Day 7 wound macrophages. Wound macrophages did not produce IL-10. The cytokines considered necessary for alternative activation of macrophages,IL-4 and IL-13, were not detected in the wound environment and were not produced by wound cells.Wound macrophages did not contain PStat6. Wound fluids inhibited IL-13-dependent phosphorylation of Stat6 and contained IL-13Ralpha2, a soluble decoy receptor for IL-13. The phenotype of wound macrophages was not altered in mice lacking IL-4Ralpha, which is required for Stat6-dependent signaling of IL-4 and IL-13.Wound macrophages exhibit a complex phenotype,which includes traits associated with alternative and classical activation and changes as the wound matures.The wound macrophage phenotype does not require IL-4 or IL-13.
Article
Evidence is strong that a reduction in risk for breast cancer is associated with moderate to vigorous physical activity (PA); however, there is limited understanding of the role of type, intensity, duration, and frequency of PA and their mechanisms in accounting for this health benefit. The objective of this review is to stimulate investigations of candidate mechanisms that may account for the effects of the intensity and duration of aerobic PA on breast cancer risk and tumor burden. Three hypotheses are considered: 1) the mTOR network hypothesis: PA inhibits carcinogenesis by suppressing the activation of the mTOR signaling network in mammary carcinomas; 2) the hormesis hypothesis: the carcinogenic response to PA is nonlinear and accounted for by a physiological cellular stress response; and 3) the metabolic reprogramming hypothesis: PA limits the amount of glucose and glutamine available to mammary carcinomas thereby inducing apoptosis because tumor-associated metabolic programming is reversed. To link these hypotheses to systemic effects of PA, it is recommended that consideration be given to determining: 1) what contracting muscle releases into circulation or removes from circulation that would directly modulate the carcinogenic process in epithelial cells; 2) whether the effects of muscle contraction on epithelial cell carcinogenesis are exerted in an endocrine, paracrine, autocrine, or intracrine manner; and 3) if the effects of muscle contraction on malignant cells differ from effects on normal or premalignant cells that do not manifest the hallmarks of malignancy.
Article
The influence of physical exercise on the tumortoxicity of peritoneal murine macrophages (PMM) was investigated. The tumortoxic activity was discriminated into cytostatic and cytolytic effects. Cytostatic activity of PMM on tumor cells in vitro was studied using the proliferation assay of S-180 sarcoma cells. Cytolytic activity was monitored using the method of the slow form of antibody-dependent cellular cytotoxicity (ADCC) on SW 707 tumor cells. After a single exhaustive running session an increased cytostatic activity of PMM was observed as compared to PMM of sedentary animals. In PMM mediated ADCC no difference was detected between trained and untrained animals. It is concluded that physical exercise is a complex stimulus for macrophages that, at least in parts, triggers their cytotoxic activity against tumor cells.
Macrophages derived from human connective tissue were assayed for their enzyme content and phagocytic activity after physical exercise. A single exhaustive endurance-running test caused increased phagocytic and enzymatic activities of the macrophages. Thus, an exercise challenge activates the functional status of the cells. This effect of physical exercise on macrophages is inconsistent with the practical experience that high performance athletes suffer more frequently from harmless infectious diseases.
Article
This study examined the effects of two doses of exercise on tumor incidence and progression, and the number and activity of intratumoral phagocytic cells (80% macrophages [M phi's]). Male mice were randomly assigned to control (CON), moderate (MOD) or exhaustive (EXH) treadmill running. Mice were inoculated subcutaneously with 2.5 x 10(5) mammary adenocarcinoma cells after 3 d of running (3 h after the last run at a point when enhancement in M phi cytotoxicity is observed). This tumor was chosen due to its susceptibility to M phi inhibition in vitro and in vivo. Mice continued daily running for 14 d. Food intakes were higher during the last 3 d in MOD and EXH, but body weights were no different. Flow cytometer analysis of tumor masses revealed that MOD had greater numbers of phagocytic cells (vs EXH) with slightly higher phagocytic activities (vs CON and EXH) (P < 0.05). However, no group differences in tumor appearance were seen except on day 7 when CON had less observable tumors than MOD and EXH (P < 0.05). Tumor size was also not different between groups at any point. These results indicate that moderate exercise can increase the phagocytic capacity of intratumoral phagocytic cells, but these changes had no apparent effect on tumor incidence or progression in this study.
Article
Recent evidence suggests that exercise affects macrophage functions and that amount of exercise may be important. We determined effects of moderate (MOD) and exhaustive treadmill running (EXH) on 1) ability of macrophages to become activated for antitumor cytotoxicity after injection of heat-inactivated Propionibacterium acnes in vivo, 2) macrophage responsiveness to activating agents lipopolysaccharide and interferon-gamma, and 3) role of glucocorticoids and various macrophage metabolic products in modulating cytotoxicity in exercised animals. Male C3H/HeN mice were randomly assigned to MOD (18 m/min, 5% grade, 30 min/day) or EXH (18-35 m/min, 5%, 2-4 h) on a motor-driven treadmill. Control animals were kept in simulated treadmill lanes located directly over the runners. In general, both MOD and EXH increased cytotoxicity (42 and 22%, respectively, across all experiments; P < 0.05). Enhanced cytotoxicity was not due to altered macrophage adherence, tumor necrosis factor-alpha, interleukin-1 beta, or reactive oxygen species. Reactive nitrogen species were responsible for enhanced toxicity in EXH only. Macrophage cytotoxicity was further increased by lipopolysaccharide and interferon-gamma to a similar maximal level that was the same in all groups. Plasma corticosterone was elevated two- and fourfold in MOD and EXH, respectively, but there was no correlation between plasma corticosterone and macrophage cytotoxicity when compared across all groups even though cells were sensitive to steroid-mediated suppression in vitro. However, consistent with a corticosterone effect, EXH reduced the number of peritoneal macrophages elicited during P. acnes inflammation and abolished the typical exercise-induced increase in cytotoxicity of activated macrophages.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
This study determined the effects of exercise on the ability of inflammatory macrophages to inhibit tumor cell growth in vitro (macrophage cytotoxicity). Thioglycollate injection (1 ml ip) was used as an inflammatory challenge and to partially activate macrophages for cytotoxicity. Inbred male C3H/HeN mice (n = 180) exercised moderately (MOD, 18 m/min, 30 min/day, 5% grade) or to exhaustion (EXH, 18-35 m/min, 2-4 h, 5% grade) on a motor-driven treadmill for 3 consecutive days after injection. Control (CON) mice were kept in stimulated treadmill lanes directly over the runners. Mice were killed immediately or 3 or 8 h postexercise. Macrophages from both MOD and EXH exercise groups manifested significantly (P < 0.05) enhanced (approximately 50%) cytotoxicity compared with those from CON group at all time points postexercise. This potentially beneficial exercise effect was not related to macrophage production of interleukin-1 beta, reactive nitrogen or oxygen intermediates, or number of macrophages in the assay but may have been manifested, in part, by tumor necrosis factor-alpha. Plasma corticosterone was significantly elevated immediately postexercise in MOD and EXH compared with CON mice; however, no evidence existed for an immuno-suppressive effect of corticosterone on macrophage cytotoxicity, perhaps because of insensitivity of inflammatory macrophages to glucocorticoid suppression seen in vitro. These data only partially support the "inverted U hypothesis," which states that moderate exercise may enhance, whereas very heavy exercise or a lack of exercise may attenuate, the immune response. Further study is needed to determine the physiological significance of these findings and the effects of exercise on macrophage subsets sensitive to glucocorticoid suppression (i.e., fully activated macrophages).
Article
The purpose of this investigation was to determine the effects of different doses of exercise on the ability of Propionibacterium acnes (P. acnes) to induce major histocompatibility complex (MHC) II antigen expression on macrophages (M phi's). Pathogen-free male Balb/c mice were exercised on a treadmill moderately (MOD, 15-17 m/min, 5% grade, 30 min/day) or exhaustively (EXH, 15-40m/min, 5% grade, 2-4hr/day) for a period of 7 days during P. acnes-induced inflammation. A control group (CON) consisted of animals exposed to the treadmill environment and handling. Sub-optimal (0.03 mg/g b.wt., i.p.) and optimal (0.08 mg/g b.wt.) doses of P. acnes were used to increase M phi MHC II expression. Animals were sacrified on Day 7 and M phi's were harvested by peritoneal lavage. Direct immunofluorescent staining was performed by incubating peritoneal exudate cells (10[6]) with an FITC-labeled anti-mouse MHC II (I-A[d]) antibody. Basal expression of MHC II was not affected by exercise. There were no significant differences among the groups in the percentage of M phi's expressing MHC II at any dose of P. acnes. However, EXH significantly (p < 0.05) suppressed the expression (mean fluorescent intensity, MFI) of MHC II when compared to MOD (37.1+/-1.95 [mean+/-sem] vs 49.1+/-2.15, p < 0.05) at the suboptimal P. acnes dosage. At the optimal P. acnes dose, both MOD and EXH significantly suppressed (27+/-1.6, 25+/-2.2 and 41.5+/-3.2, for EXH, MOD, and CON, respectively, p<0.0001) P. acnes-induced M phi MHC II MFI. Plasma corticosterone was highly (r=-0.71, p = 0.001) inversely correlated with M phi MHC II expression. However, exercise failed to affect P. acnes-induced production of interferon-gamma. These data suggest that, dependent on the degree of stimulation, exercise can negatively affect M phi expression of MHC II, an effect that may be detrimental to the M phi's ability to present antigen to T lymphocytes.
Article
Age-dependent tumor cytolytic functions of tumor-associated macrophages (TAM) obtained from mice bearing different stages of Dalton's lymphoma (DL), a spontaneous T cell lymphoma, were studied. Mice were separated into three groups on the basis of their reproductive status as indicator of age: young (prereproductive); adult (reproductive) and old (postreproductive). DL was injected (1 x 10(5) cells/mouse) intraperitoneally in mice; days 4, 10 and 16 from the day of injection were referred to as early, mid and late tumor stages, respectively. Normal peritoneal macrophages and macrophages isolated from the ascitic fluid of DL-bearing mice (TAM); 1 x 10(5) cells activated with lipopolysaccharide (LPS) plus interferon-gamma (IFN-gamma) and assayed for age-dependent alterations in macrophage tumoricidal functions such as: tumor cell binding, cytotoxicity, production of reactive nitrogen intermediates (RNI), expression of inducible nitric oxide synthase (iNOS) and oncostatin-M (OSM) were observed. TAM from old mice were observed to be inhibited with respect to tumor cell binding, cytotoxicity and expression of iNOS and OSM, as compared to macrophages of young and adult mice. TAM obtained from early tumor stages showed augmented tumor cytotoxicity as well as enhanced expression of iNOS and OSM in all the age groups. This effect was most pronounced in the TAM obtained from adult mice and least in the TAM obtained from old mice. The reasons for the observed difference are discussed. These observations should be helpful in understanding the effect of progressive tumor growth and age on the functions of TAM and their responsiveness towards therapeutic manipulations.