Search

Colorectal cancer (CRC) is the third most common cancer worldwide, and its incidence is increasing. Inflammation associates with the pathogenesis of cancer by several mechanisms. Toll-like receptors (TLRs) mediate and regulate the inflammatory response and their role in cancer progression has been established in many cancers. This study aimed to clarify the roles of TLR2 and TLR4 and their significance in the development, progression, and prognosis of CRC in relation to inflammation in a series of 149 CRC patients operated in Oulu University Hospital (2006–2010). We characterized the tissue expression in CRC tumors and serum levels of TLR2 and TLR4, and the associations of expression patterns with tumor features and the prognosis of cancer. We found downregulation of TLR4 and upregulation of TLR2 in CRC, and low expression of TLR4 in the invasive front of the tumor predicted poor prognosis and metastatic disease. Serum TLR2 levels were inversely associated with systemic inflammation in patients with CRC, and our findings suggested that serum TLR2 levels might depend more on normal colorectal mucosa contributions than on tumor tissue. Also, the mean serum TLR4 levels were lower in patients than in controls. We also found that tumor necrosis in CRC associated with low TLR4 expression in carcinoma epithelium, and low TLR4 expression associated with systemic inflammation. Tumoral TLR2 expression did not correlate with necrosis from systemic inflammation, but low expression of TLR2 in normal mucosa was linked to indicators of systemic inflammation, supporting the concept that the normal colon mucosa may contribute to the regulation of systemic inflammation. In conclusion, TLR2 and TLR4 showed divergent roles in CRC. TLR2 was upregulated and TLR4 downregulated in CRC. Downregulation of TLR4 was related to tumoral necrosis and adverse prognosis. High normal mucosa TLR2 expression associated with high serum TLR2 concentration and signs of lower systemic inflammation. Tiivistelmä Paksu- ja peräsuolisyöpä on maailmanlaajuisesti kolmanneksi yleisin syöpä ja sen ilmaantuvuus on kasvussa. Tulehdus vaikuttaa syövän syntyyn ja kehitykseen useilla mekanismeilla. Kohonnut elimistön tulehdusvaste liittyy huonoon ennusteeseen, mutta paikallinen tulehdus kasvaimen leviämisvyöhykkeessä on yhdistetty parempaan selviytymiseen. Tollin kaltaiset reseptorit (TLR) välittävät ja säätelevät tulehdusvastetta, ja niiden merkitys syövän etenemisessä on osoitettu monessa syövässä. Tämän tutkimuksen tarkoitus oli selvittää TLR2:n ja TLR4:n rooleja ja merkitystä tulehduksen kannalta paksu- ja peräsuolisyövän kehittymisessä, etenemisessä ja ennusteessa 149:n Oulun yliopistollisessa sairaalassa vuosina 2006–2010 leikatun potilaan aineistossa. Määritimme TLR2:n ja TLR4:n ilmentymistasot syöpäkasvaimissa ja niiden seerumitasot sekä näiden yhteyksiä kasvaimen ominaisuuksiin ja syövän ennusteeseen. TLR4:n ilmentyminen oli vähentynyt ja TLR2:n lisääntynyt kasvaimissa, ja matala TLR4:n ilmentyminen kasvaimen leviämisvyöhykkeessä liittyi huonompaan ennusteeseen ja etäpesäkkeiseen tautiin. TLR2:n seerumitasot korreloivat käänteisesti elimistön tulehdusvasteeseen syöpäpotilailla, ja löydöksemme viittaa siihen, että TLR2:n seerumipitoisuuteen myötävaikuttaa enemmän normaalin paksusuolen limakalvo kuin kasvainkudos. TLR4:n seerumitasot olivat matalammat potilailla verrattuna verrokkeihin. Myös kasvaimen kuolio liittyi matalaan TLR4:n ilmentymiseen kasvaimessa, mikä puolestaan oli yhteydessä elimistön tulehdukseen. Kasvaimen TLR2 ilmentyminen ei liittynyt kasvaimen kuolioon tai tulehdukseen, mutta matala TLR2:n ilmentyminen normaalilla limakalvolla liittyi elimistön tulehdusta kuvaaviin muuttujiin, mikä tukee ajatusta normaalin limakalvon vaikutuksesta elimistön tulehduksen säätelyssä. Yhteenvetona voidaan todeta, että TLR2:n ja TLR4:n roolit paksu- ja peräsuolisyövässä ovat erilaiset: TLR2:n ilmentyminen lisääntyy ja TLR4:n vähenee. TLR4:n ilmentymisen väheneminen liittyy kasvaimen kuolioon ja huonompaan ennusteeseen. Normaalin limakalvon korkea TLR2:n ilmentyminen on yhteydessä korkeaan seerumin TLR2-tasoon ja merkkeihin matalasta elimistön tulehdusasteesta.

Millions of women globally use combined oral contraceptives (COCs) for contraception and the treatment of various conditions. As women may use these preparations for decades, it is essential that they are provided with products that are both effective and safe with minimal side effects. Traditional ethinylestradiol (EE)-based COCs are known to affect metabolism, inflammation, hepatic protein synthesis, and blood coagulation. COCs containing natural estrogens have recently been introduced to the market, offering an interesting new alternative to EE-based COCs. The present studies aimed to investigate the differences of EE- and estradiol valerate (EV)-based COCs in the serum proteome, inflammation, lipids, and ovarian and adrenal hormones. The studies were based on a randomized, controlled, multicenter clinical trial, SYLVI. Altogether, 59 healthy young women were randomized to use either EE+dienogest (DNG) (n=20), EV+DNG (n=20), or DNG only (n=19) continuously for 9 weeks. Fasting serum samples were collected at baseline and the fifth and ninth weeks. We performed an untargeted proteomic analysis and analyzed changes in the inflammatory markers high-sensitivity CRP and pentraxin 3, lipid measurements, gonadotropins, ovarian and adrenal steroids, anti-Müllerian hormone, sex hormone-binding globulin (SHBG), and corticosteroid-binding globulin (CBG). Our results showed that the number of affected proteins in the circulation during EE+DNG use was multifold compared with the natural estrogen-based EV+DNG and DNG-only preparations. The pathways most affected during EE+DNG use were the complement pathway, acute phase signaling response, metabolism-related pathways, and coagulation system. A natural-estrogen-based COC also had significantly milder effects on low-grade inflammation, lipid profile, gonadotropins, androgens, cortisol, and binding protein (SHBG, CBG) synthesis compared with the synthetic EE+DNG preparation. This thesis highlights the neutral effects of natural estrogen in a COC compared with the synthetic and highly potent EE. To date, the choice of COC is based mainly on the properties of progestin components. However, emerging data, suggesting the milder metabolic impact of natural estrogens, promote the consideration of estrogen when prescribing COCs. The results encourage further research and development of natural-estrogen-based COCs. Tiivistelmä Miljoonat naiset käyttävät yhdistelmäehkäisyvalmisteita sekä raskauden ehkäisyyn että erilaisten gynekologisten oireiden hoitoon usein jopa vuosikymmenten ajan. Näin ollen on tärkeää kehittää tehokkaita ja turvallisia valmisteita, joilla on mahdollisimman vähän sivuvaikutuksia. Perinteisesti yhdistelmäehkäisyvalmisteet ovat sisältäneet etinyyliestradiolia (EE), jonka on todettu heikentävän muun muassa rasva-aineenvaihduntaa ja korostavan matala-asteista tulehdusta. Hiljattain kehitetyt, luonnollisempia estrogeeneja sisältävät valmisteet tarjoavat uuden, mielenkiintoisen vaihtoehdon aiemmille yhdistelmille. Väitöskirjan pohjana on satunnaistettu ja kontrolloitu kliininen lääketutkimus SYLVI. 59 naista käyttivät 9 viikkoa yhtäjaksoisesti yhtä seuraavista valmisteista: EE+dienogesti (DNG, n=20), estradiolivaleraatti (EV)+DNG (n=20) tai pelkkä DNG (n=19). Paastoverinäytteet otettiin ennen valmisteen käyttöä sekä viidennellä ja yhdeksännellä käyttöviikolla. Valmisteiden vaikutuksia selvitettiin kohdentamattomalla proteomiikka-analyysillä sekä mittaamalla tulehdusmerkkiaineita ja rasva-arvoja. Hormonisäätelymuutoksia selvitettiin mittaamalla munasarjojen ja lisämunuaiskuoren steroidihormoneja, gonadotropiinit, anti-Müller-hormoni, sukupuolihormoneja sitova proteiini (SHBG) ja kortikosteroideja sitova proteiini (CBG). Tutkimusjakson aikana EE-pohjaisen valmisteen muuttamien proteiinien määrä oli moninkertainen verrattuna estradiolipohjaiseen valmisteeseen ja pelkkään progestiiniin. Nämä muuttuneet proteiinit liittyivät komplementtijärjestelmään, akuutin faasin signalointiin, aineenvaihdunnan säätelyyn sekä veren hyytymistekijöihin. Luonnollisemmalla estradiolipohjaisella yhdistelmällä oli lievemmät vaikutukset myös matala-asteiseen tulehdukseen, rasva-arvoihin, gonadotropiineihin sekä steroidihormoneihin ja näiden kuljettajaproteiineihin (SHBG, CBG) verrattuna synteettiseen EE-yhdistelmään. Tämä väitöskirjatutkimus korostaa luonnolliseen estrogeeniin pohjautuvan yhdistelmäehkäisyn neutraalimpia kokonaisvaikutuksia synteettiseen ja hyvin tehokkaaseen EE:iin verrattuna. Tähän saakka yhdistelmäehkäisyvalmisteen valinta on perustunut lähinnä eri progestiinien ominaisuuksiin, mutta karttuvan tiedon valossa myös estrogeenikomponentti tulisi huomioida. Tutkimustulokset kannustavat tutkimaan ja kehittämään luonnollista estrogeenia sisältäviä valmisteita.

Saccular intracranial aneurysm (sIA) rupture leads to subarachnoid haemorrhage and is preceded by chronic inflammation and atherosclerotic changes of the sIA wall. Increased lymphangiogenesis has been detected in atherosclerotic extracranial arteries and in abdominal aortic aneurysms, but the presence of lymphatic vessels in sIAs has remained unexplored. Here we studied the presence of lymphatic vessels in 36 intraoperatively resected sIAs (16 unruptured and 20 ruptured), using immunohistochemical and immunofluorescence stainings for lymphatic endothelial cell (LEC) markers. Of these LEC-markers, both extracellular and intracellular LYVE-1-, podoplanin-, VEGFR-3-, and Prox1-positive stainings were detected in 83%, 94%, 100%, and 72% of the 36 sIA walls, respectively. Lymphatic vessels were identified as ring-shaped structures positive for one or more of the LEC markers. Of the sIAs, 78% contained lymphatic vessels positive for at least one LEC marker. The presence of LECs and lymphatic vessels were associated with the number of CD68+ and CD163+ cells in the sIA walls, and with the expression of inflammation indicators such as serum amyloid A, myeloperoxidase, and cyclo-oxygenase 2, with the presence of a thrombus, and with the sIA wall rupture. Large areas of VEGFR-3 and α-smooth muscle actin (αSMA) double-positive cells were detected in medial parts of the sIA walls. Also, a few podoplanin and αSMA double-positive cells were discovered. In addition, LYVE-1 and CD68 double-positive cells were detected in the sIA walls and in the thrombus revealing that certain CD68+ macrophages are capable of expressing LEC markers. This study demonstrates for the first time the presence of lymphatic vessels in human sIA walls. Further studies are needed to understand the role of lymphatic vessels in the pathogenesis of sIA.

We investigated the associations of physical activity (PA), sedentary time (ST), and diet quality with biomarkers of inflammation in 390 children (192 girls, 198 boys) aged 6–8 years. PA energy expenditure (PAEE), light PA, moderate PA (MPA), vigorous PA (VPA), moderate-to-vigorous PA (MVPA), and ST were assessed by combined movement and heart rate sensor. Finnish Children Healthy Eating Index was calculated using data from 4 d food records. Body fat percentage (BF%) was measured by dual-energy X-ray absorptiometry. High-sensitivity C-reactive protein (Hs-CRP), leptin, interleukin-6 (IL-6), adiponectin, tumour necrosis factor-α, and glycoprotein acetyls were measured from fasting blood samples. PAEE, MPA, VPA, and MVPA were inversely associated with hs-CRP (β=−191 to −139, 95% CI=−0.294 to −0.024), leptin (β=−0.409 to −0.301, 95% CI=−0.499 to −0.107), IL-6 (β=−0.136 to −0.104, 95% CI=−0.240 to −0.001) and PAEE, MPA, and MVPA were inversely associated with glycoprotein acetyls (β=−0.117 to −0.103, 95% CI=−0.213 to −0.001). ST was directly associated with hs-CRP (β=0.170, 95% CI=0.070–0.269), leptin (β=0.355, 95% CI=0.265–0.445), and IL-6 (β=0.105, 95% CI=0.005–0.205). VPA was inversely associated with hs-CRP, leptin, and IL-6 in children with higher BF% (β=−0.344 to −0.181, 95% CI=−0.477 to −0.033) but not among children with lower BF% (β=−0.007–0.033, 95% CI=−0.183–0.184). In conclusion, PA was inversely and ST directly associated with circulating levels of biomarkers of inflammation among children. Furthermore, we observed that PA was inversely associated with these biomarkers for inflammation in children with a higher BF%. Highlights Systemic inflammation, as indicated by increased circulating concentrations of biomarkers for inflammation, may be important in causal pathways leading to insulin resistance, sub-clinical atherosclerosis, and eventually clinical manifestations of cardiovascular diseases. Higher levels of physical activity and lower levels of sedentary time were associated with more favourable inflammatory profile. Body fat percentage modified these associations and especially vigorous intensity physical activity was inversely associated with biomarkers of inflammation on children with higher body fat percentage but not in children with lower body fat percentage.

The causes and pathophysiological mechanisms of building-related symptoms (BRS) are unclear. The aim of this cross-sectional study was to investigate the association between intrinsic in vitro toxicity in classrooms and teachers’ work-related symptoms. Teachers from 15 Finnish schools responded to the symptom survey. The boar sperm motility inhibition assay, a sensitive indicator of mitochondrial dysfunction, was used to measure the toxicity of wiped dust and cultured microbial fallout samples collected from the teachers’ classrooms. 231 teachers whose classroom toxicity data had been collected responded to the questionnaire. The Poisson regression model showed that teachers’ work-related BRS were 2.8-fold (95% CI: 1.6–4.9) higher in classrooms with highly toxic dust samples compared to classrooms with non-toxic dusts. The rate ratio of work-related BRS was 1.8 (95% CI: 1.1–2.8) for toxic microbial samples. Logistic regression analysis showed that classroom dust toxicity was statistically significantly associated with the following 12 symptoms (adjusted odds ratios in parentheses): nose stuffiness (4.1), runny nose (6.9), hoarseness (6.4), globus sensation (9.0), throat mucus (7.6), throat itching (4.4), shortness of breath (12.2), dry cough (4.7), wet eyes (12.7), hypersensitivity to sound (7.9), difficulty falling asleep (7.6), increased need for sleep (7.7). Toxicity of cultured microbes was associated with nine symptoms (adjusted ORs in parentheses): headache (2.3), nose stuffiness (2.2), nose dryness (2.2), mouth dryness (2.8), hoarseness (2.2), sore throat (2.8), throat mucus (2.3), eye discharge (10.2), increased need for sleep (3.5). The toxicity of classroom dust and airborne microbes in boar sperm motility inhibition assay significantly increased teachers’ risk of work-related symptoms. The results support the hypothesis based on previous literature showing that exposure to boar sperm-toxic substances can cause mitochondrial dysfunction, oxidative stress, immunological inflammation, activation and sensitization of chemosensory C-fibers, and neurogenic inflammation. These findings contribute a new perspective to the research field of indoor adverse exposure and pathophysiological processes in exposed, symptomatic individuals. Tiivistelmä Rakennukseen liittyvien oireiden (building-related symptoms, BRS) aiheuttajat ja syntymekanismit ovat edelleen avoinna. Tässä poikkileikkaustutkimuksessa selvitettiin koululuokan toksisuuden vaikutusta opettajien työympäristöön liittyvien oireiden riskiin. Opettajien työympäristöön liittyvät oireet kartoitettiin sähköisellä kyselyllä 15 suomalaiskoulussa. Luokkahuoneiden sisäilman mikrobiviljelmien ja laskeumapölyjen toksisuutta mitattiin sian siittiötestillä, joka on herkkä mitokondriotoksisuuden tunnistusmenetelmä. Kyselyyn vastasi 231 valintakriteerit täyttävää opettajaa, joiden luokkahuoneista oli toksisuustieto. Työympäristöön liittyvistä BRS-oireista oli viimeisen vuoden aikana kärsinyt yli puolet opettajista, ja yli kolmannes pöly- ja mikrobinäytteistä oli toksisia. Sukupuoli-, tupakointi-, atopia- ja ikävakioidun Poissonin regressiomallin mukaan opettajilla, joiden luokkahuoneen pöly oli toksisinta, työympäristöön liittyvien BRS-oireiden määrä oli 2,8-kertaa suurempi (95 %:n luottamusväli eli CI 1,6–4,9) kuin opettajilla, joiden luokkahuoneen pöly oli ei-toksista. Vastaavasti luokkahuoneissa, joissa havaittiin toksisia mikrobeja, BRS-oireiden määrä oli 1,8-kertaa suurempi (95 % CI 1,5–2,1) kuin luokkahuoneissa, joissa toksisia mikrobeja ei havaittu. Vakioidun negatiivisen binomiaalisen monitasomallin mukaan opettajien työympäristöön liittyvät ei-perinteiset BRS-oireet olivat toksisimpien pölyjen luokkahuoneissa 2,9-kertaiset (95 % CI 1,2–7,3) verrattuna ei-toksisten pölyjen luokkahuoneisiin ja toksisten mikrobien luokkahuoneissa 1,8-kertaiset (95 % CI 1,1–2,8) verrattuna ei-toksisten mikrobien luokkiin. Pölyn toksisuus oli yhteydessä 12 työympäristöön liittyvään oireeseen (vetosuhteet ja 95 %:n CI:t sulkeissa): nenän tukkoisuus (4,1; 1,2–13), nuhavuoto (6,9; 1,8–27), äänen käheys (6,4; 1,9–21), palan tunne kurkussa (9,0; 1,7–47), nielun limaisuus (7,6; 2,2–26), kurkun kutina (4,4; 1,1–18), hengenahdistus (12,2; 1,9–77), kuiva yskä (4,7; 1,3–17), silmien vetistys (12,7; 1,4–112), ääniyliherkkyys (7,9; 1,7–37), nukahtamisvaikeus (7,6; 1,9–30) ja lisääntynyt unen tarve (7,7; 2,1–29). Mikrobiviljelmien toksisuus oli yhteydessä yhdeksään työympäristöön liittyvään oireeseen: päänsärky (2,3; 1,1–4,8), nenän tukkoisuus (2,2; 1,1–4,4), nenän kuivuus (2,2; 1,1–4,5), suun kuivuus (2,8; 1,1–6,7), äänen käheys (2,2; 1,1–4,3), kurkkukipu (2,8; 1,1–7,3), nielun limaisuus (2,3; 1,1–4,7), silmien rähmiminen (10,2; 2,0–51) ja lisääntynyt unen tarve (3,5; 1,0–12). Koulun sisäilman mikrobien ja laskeumapölyn siittiötoksisuudet ovat merkittäviä opettajien työympäristöön liittyvien oireiden riskitekijöitä. Tulokset tukevat käytettävissä olevaan kirjallisuuteen perustuvaa hypoteesia, jonka mukaan siittiötoksinen altistuminen voi aiheuttaa elimistössä mitokondrioiden toimintahäiriöitä, oksidatiivista stressiä, immunologista tulehdusta, kemosensoristen C-hermosäikeiden aktivaatiota ja herkistymistä sekä neurogeenista tulehdusta. Tämä avaa uusia mahdollisuuksia sisäilma-altisteisiin liittyvän terveysriskin sekä BRS-oireiden syiden, mekanismien ja hoitomuotojen tutkimiseen.

Purpose Whether elite athletes, who have been exposed to vigorous-intensity exercise combined with other stressors, have elevated systemic low-grade inflammation, remains largely unclear. To address this question, we studied the levels of six inflammatory cytokines as potential biomarkers of a low-grade inflammatory state in elite athletes after an 11-month training and competition season. Methods We collected sera from 27 Finnish elite cross-country skiers and 27 gender- and age-matched, moderately-exercising controls. The serum concentrations of C-reactive protein (CRP), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), glycoprotein acetyls (GlycA), interleukin 10 (IL-10), and interferon gamma (IFN-γ) cytokines were quantified as surrogate markers of low-grade inflammation. Results The athletes were found to have significantly lower concentrations of CRP (P = 0.0232) and higher concentrations of IL-10, TNF-α, and IFN-γ (P = 0.0097, P = 0.0256, and P = 0.0185, respectively) than the controls. No significant differences between athletes and controls were detected in the concentrations of IL-6 and GlycA. The inflammatory score (IS) did not differ significantly between athletes and controls. Conclusion The results of this study argued against the hypothesis of a significant chronic low-grade inflammation in response to prolonged high-performance exercise among elite endurance athletes.

Pinosylviini on stilbenoideihin kuuluva luonnollinen yhdiste, jota esiintyy erityisesti mäntyjen sydänpuussa. Stilbenoidit ovat fenolisia yhdisteitä ja niiden pääasiallisena tehtävänä on toimia suojaavana tekijänä kasveissa erinäisiä taudinaiheuttajia ja muita haitallisia tekijöitä vastaan. Niillä on myös ihmisen terveyttä edistäviä vaikutuksia; tutkimusten mukaan stilbenoidit voivat esimerkiksi rauhoittaa tulehdusta estämällä tulehduksellisten makrofagien aktivaatiota. Makrofagit toimivat ihmisen elimistössä syöjäsoluina ja ne reagoivat ympäristönsä muutoksiin erilaistumalla eli polarisoitumalla karkeasti jaettuna joko M1-tyypin eli klassisesti aktivoituneen tai M2-tyypin eli vaihtoehtoisesti aktivoituneen makrofagin suuntaan. Klassisesti aktivoituneet makrofagit ovat proinflammatorisia eli tulehduksellisia makrofageja, joita esiintyy erityisesti infektioiden ja tulehdussairauksien aikana. Vaihtoehtoisesti aktivoituneet makrofagit toimivat ensisijaisesti antiinflammatorisina eli ne osallistuvat tulehdustilan rauhoittamiseen ja kudosvaurion korjaamiseen. Pinosylviinin on todettu estävän makrofagien M1-tyypin aktivaatiota, kun taas vaikutuksia M2-tyypin aktivoitumiseen ei ole aiemmin tutkittu. Tässä tutkimuksessa tarkastellaan pinosylviinin vaikutusta makrofagien M2-tyypin aktivoitumiseen. Tutkimuksen hypoteesina on, että pinosylviinillä pystyisi, M1-tyypin aktivaation estämisen lisäksi, lisäämään makrofagien M2-tyypin aktivaatiota. Glukokortikoidit, jotka ovat paljon käytettyjä, tehokkaita tulehdusta rauhoittavia lääkkeitä, omaavat kuvatunlaisia makrofagien polarisaatiota suuntaavia vaikutuksia. Niillä on lisäksi monia muitakin tulehdusta rauhoittavia vaikutuksia, mutta laaja-alaisten vaikutusten vuoksi glukokortikoideilla on myös paljon käyttöä rajoittavia haittavaikutuksia. Täten olisi hyödyllistä löytää yhdisteitä, jotka vaikuttavat kohdennetummin tulehdusta rauhoittaen. Tässä tutkimuksessa pinosylviinin vaikutuksia makrofagien erilaistumiseen tutkittiin hiiren J774- ja humaani U937-makrofageissa. Tutkimuksessamme käytettiin lipopolysakkaridia (LPS) M1-tyypin ja interleukiini-4:ä (IL-4) M2-tyypin aktivaation indusoimiseksi makrofageissa. Makrofagien erilaistumista arvioitiin mittaamalla M1- ja M2-tyypin makrofageille tyypillisten merkkiaineiden ilmenemistä. Hypoteesin mukaisesti pinosylviini lisäsi M2-tyypin makrofagimerkkiaineiden, arginaasi-1:n (Arg-1, engl. arginase-1) ja C-tyypin 1 mannoosireseptorin (MRC1, engl. Mannose receptor C-type 1), ilmenemistä hiiren J774-makrofageissa. Sama ilmiö nähtiin myös humaani U937-makrofageissa, joissa pinosylviini lisäsi humaanisoluille tyypillisten M2-tyypin makrofagimerkkiaineiden, CC-perheen kemokiiniligandien 17 ja 26 (CCL17 ja CCL26, engl. C-C motif chemokine ligands 17 and 26), tuottoa. Pinosylviini myös lisäsi tunnetun M2-tyypin aktivaation signalointireitin osan, PPAR-γ:n (peroksisomiproliferaattorilla aktivoituva gammareseptori, engl. Peroxisome proliferator-activated receptor gamma), ilmenemistä. Pinosylviini esti M1-tyypin makrofagimerkkiaineiden, NO:n eli typpioksidin, monosyyttien kemotaktisen proteiini 1:n (MCP-1, engl. Monocyte chemoattractant protein 1) sekä interleukiini-6:n (IL-6, engl. Interleukin-6), ilmenemistä J774-makrofageissa. Humaani U937-makrofageissa pinosylviini esti M1-tyypin merkkiaineiden, tuumorinekroositekijä alfan (TNF-α, engl. Tumor necrosis factor alpha) ja interleukiini-1β:n (IL-1β, engl. Interleukin-1β), tuottoa. Pinosylviini myös esti NF-κB-signalointireittiä (engl. Nuclear factor kappa B), joka on keskeinen osa M1-tyypin aktivoitumisessa. Tulokset siis osoittavat, että pinosylviini suuntaa makrofagien polarisaatiota proinflammatorisesta M1tyypistä anti-inflammatoriseen M2-tyyppiin ja voisi näin rauhoittaa tulehdusta ja käynnistää kudosvaurioiden paranemisprosessia. Nämä vaikutukset mahdollistavat pinosylviinin hyödyntämisen erinäisten tulehdustilojen lääkehoidon kehittämisessä tulevaisuudessa.

Little is known how acute exercise-induced inflammation and metabolic stress affect immune cell bioenergetics and the portion of its components. Therefore, we investigated acute effects of eccentric-only (E), concentric-only (C) and combined eccentric-concentric resistance exercise (E + C) bouts on cellular respiration of peripheral blood mononuclear cells (PBMCs). Twelve strength-trained young men performed bench press resistance exercises in randomized order. Venous blood samples were drawn at pre-, 5 min post- and 24 h post-exercise. Several PBMC respiration states were measured using high-resolution respirometry. Levels of leukocytes, interleukin 6 (IL-6), C-reactive protein (CRP), creatine kinase (CK), blood lactate and maximum voluntary isometric force were measured from the same time points. Effects of blood lactate and pH change on bioenergetics of PBMCs were investigated ex vivo. PBMC routine respiration (p = 0.017), free routine capacity (p = 0.025) and ET-capacity (p = 0.038) decreased immediately after E + C. E responded in opposite manner 5 min post-exercise compared to E + C (p = 0.013) and C (p = 0.032) in routine respiration, and to E + C in free routine activity (p = 0.013). E + C > C > E was observed for increased lactate levels and decreased isometric force that correlated with routine respiration (R = −0.369, p = 0.035; R = 0.352, p = 0.048). Lactate and pH change did not affect bioenergetics of PBMCs. Acute resistance exercise affected cellular respiration of PBMCs, with training volume and the amount of metabolic stress appear influential. Results suggest that acute inflammation response does not contribute to changes seen in cellular respiration, but the level of peripheral muscle fatigue and metabolic stress could be explaining factors. peerReviewed

It has been shown that small doses of oral D-glyceric acid (DGA) activate mitochondrial metabolism and reduce inflammation among 50–60-year-old healthy volunteers. The present results with the same small doses reveal that after a 4-day DGA regimen, a dose of DGA activated the HO-1 pathway acutely, while enhanced inflammatory status after the 4-day DGA regimen seemed to be able to downregulate the HO-1 pathway in non-acute measurement. Blood bilirubin was strongly upregulated towards the end of the altogether 21-day study period with positive associations towards improved inflammation and reduced blood triglycerides. After the 4-day DGA regimen, hepatic inflow of blood bilirubin with albumin as the carrier was clearly upregulated in the lower-aerobic-capacity persons. At the same time also, blood triglycerides were down, pointing possibly to the activation of liver fatty acid oxidation. The combination of activated aerobic energy metabolism with transient HO-1 pathway activation and the upregulation of blood bilirubin may reduce the risks of chronic diseases, especially in aging. Furthermore, there exist certain diseases with unsatisfactorily-met medical needs, such as fatty and cholestatic liver diseases, and Parkinson’s disease, that can be possibly ameliorated with the whole-body mechanism of the action of the DGA regimen. peerReviewed

Immunological and epigenetic changes are interconnected and contribute to tumorigenesis. We determined the immunoprofiles and promoter methylation of inflammation-related genes for colitis-associated colorectal carcinomas (CA-CRC). The results were compared with Lynch syndrome (LS)-associated colorectal tumors, which are characterized by an active immune environment through inherited mismatch repair defects. CA-CRCs (n = 31) were immunohistochemically evaluated for immune cell scores (ICSs) and PDCD1 and CD274 expression. Seven inflammation-associated genes (CD274, NTSR1, PPARG, PTGS2, PYCARD, SOCS1, and SOCS2), the repair gene MGMT, and eight standard marker genes for the CpG Island Methylator Phenotype (CIMP) were investigated for promoter methylation in CA-CRCs, LS tumors (n = 29), and paired normal mucosae by multiplex ligation-dependent probe amplification. All but one CA-CRCs were microsatellite-stable and all LS tumors were microsatellite-unstable. Most CA-CRCs had a high ICS (55%) and a positive CD274 expression in immune cells (52%). NTSR1 revealed frequent tumor-specific hypermethylation in CA-CRC and LS. When compared to LS mucosae, normal mucosae from patients with CA-CRC showed significantly higher methylation of NTSR1 and most CIMP markers. In conclusion, CA-CRCs share a frequent ICShigh/CD274pos expression pattern with LS tumors. Elevated methylation in normal mucosa may indicate field cancerization as a feature of CA-CRC-associated tumorigenesis.

The accumulation of fat, especially in visceral sites, is a significant risk factor for several chronic diseases with altered cardiometabolic homeostasis. We studied how intensive long-term weight loss and subsequent weight regain affect physiological changes, by longitudinally interrogating the lipid metabolism and white blood cell transcriptomic markers in healthy, normal-weight individuals. The current study examined 42 healthy, young (age: 27.5 ± 4.0 years), normal-weight (body mass index, BMI: 23.4 ± 1.7 kg/m2) female athletes, of which 25 belong to the weight loss and regain group (diet group), and 17 to the control group. Participants were evaluated, and fasting blood samples were drawn at three time points: at baseline (PRE); at the end of the weight loss period (MID: 21.1 ± 3.1 weeks after PRE); and at the end of the weight regain period (POST: 18.4 ± 2.9 weeks after MID). Following the weight loss period, the diet group experienced a ~73% reduction (~0.69 kg) in visceral fat mass (false discovery rate, FDR −16), accompanied by anti-atherogenic effects on transcriptomic markers, decreased low-grade inflammation (e.g., as α1–acid glycoprotein (FDR = 3.08 × 10−13) and hs-CRP (FDR = 2.44 × 10−3)), and an increase in functionally important anti-atherogenic high-density lipoprotein -associated metabolites (FDR

Background: Based on earlier studies, natural metabolite D-glyceric acid (DGA) does not seem to play any role in whole-body metabolism. Nevertheless, one ethanol oxidation-related rat study with controversial results raised our interest. According to preparatory studies for the regulatory approval of DGA, some highly conserved mechanism seems to subtly activate the cellular energy metabolism. Therefore, the present 25-days double-blind human study with placebo control was initiated. Purpose: The main target in the present study with 27 healthy 50–60-year-old human volunteers was to find out whether an “acute” 4-days and a longer 21-days exogenous DGA regimen caused moderate activation of the mitochondrial energy metabolism. The simultaneous target was to find out whether a halved dose of DGA continued to be an effective regimen. Main Findings: The results revealed the following statistically significant findings: 1) plasma concentrations of metabolites related to aerobic energy production, especially lactate, were strongly reduced, 2) systemic inflammation was lowered both in 4- and 21-days, 3) mitochondria-related mRNA expressions in circulating immune cells were noticeably modulated at Day4, 4) cellular membrane integrity seemed to be sharply enhanced, and 5) cellular NADH/NAD+ -ratio was upregulated. Conclusion: Mitochondrial metabolism was clearly upregulated at the whole-body level in both 4- and 21 days. At the same time, the effect of DGA was very well tolerated. Based on received solid results, the DGA regimen may alleviate acute and chronic energy metabolic challenges in main organs like the liver, CNS, and skeletal muscles. Enhanced membrane integrity combined with lower systemic inflammation and activated metabolic flows by the DGA regimen may be beneficial especially for the aging population. peerReviewed

Toll-like receptor 5 ligand, flagellin, and vascular adhesion protein 1 (VAP-1) are involved in non-alcoholic fatty liver disease. This study aimed to determine whether VAP-1 mediates flagellin-induced hepatic fat accumulation. The effects of flagellin on adipocyte VAP-1 expression were first studied in vitro. Then, flagellin (100 ng/mouse) or saline was intraperitoneally injected into C57BL/6J (WT) and C57BL/6-Aoc3-/- (VAP-1 KO) mice on a high-fat diet twice a week every 2 weeks for 10 weeks. After that, the effects on inflammation, insulin signaling, and metabolism were studied in liver and adipose tissues. Hepatic fat was quantified histologically and biochemically. Because flagellin challenge increased VAP-1 expression in human adipocytes, we used VAP-1 KO mice to determine whether VAP-1 regulates the inflammatory and metabolic effects of flagellin in vivo. In mice, VAP-1 mediated flagellin-induced inflammation, leukocyte infiltration, and lipolysis in visceral adipose tissue. Consequently, an increased release of glycerol led to hepatic steatosis in WT, but not in KO mice. Flagellin-induced hepatic fibrosis was not mediated by VAP-1. VAP-1 KO mice harbored more inflammation-related microbes than WT mice, while flagellin did not affect the gut microbiota. Our results suggest that by acting on visceral adipose tissue, flagellin increased leukocyte infiltration that induced lipolysis. Further, the released glycerol participated in hepatic fat accumulation. In conclusion, the results describe that gut microbial flagellin through VAP-1 induced hepatic steatosis.

Saccular intracranial aneurysm (sIA) rupture leads to a disabling subarachnoid hemorrhage. Chronic inflammation and lipid accumulation in the sIA wall contribute to wall degenerative remodeling that precedes its rupture. A better understanding of the pathobiological process is essential for improved future treatment of patients carrying sIAs. Serum amyloid A (SAA) is an acute-phase protein produced in response to acute and chronic inflammation and tissue damage. Here, we studied the presence and the potential role of SAA in 36 intraoperatively resected sIAs (16 unruptured and 20 ruptured), that had previously been studied by histology and immunohistochemistry. SAA was present in all sIAs, but the extent of immunopositivity varied greatly. SAA immunopositivity correlated with wall degeneration (p = 0.028) and rupture (p = 0.004), with numbers of CD163-positive and CD68-positive macrophages and CD3-positive T lymphocytes (all p

Treatment of brain cancer, glioma, can cause cognitive impairment as a side‐effect, possibly because it disrupts the integrity of the hippocampus, a structure vital for normal memory. Radiotherapy is commonly used to treat glioma, but the effects of irradiation on the brain are still poorly understood, and other biological effects have not been extensively studied. Here we exposed healthy adult male rats to small and moderate‐dose irradiation of the head. We found no effect of irradiation on systemic inflammation, weight gain or gut microbiota diversity, although it increased the abundance of Bacteroidaceae family, namely Bacteroides genus in the gut microbiota. Irradiation had no effect on long‐term potentiation in the CA3‐CA1 synapse or endogenous hippocampal electrophysiology, but it did reduce adult hippocampal neurogenesis and impaired short‐term spatial recognition memory. However, no overall cognitive impairment was observed. To summarize, our results suggest that in adult male rats head irradiation does not compromize health or cognition overall even though the number of new, adult‐born hippocampal neurons is decreased. Thus, the sole effects of head irradiation on the body, brain and cognition might be less harmful than previously thought, and the cognitive decline experienced by cancer patients might originate from physiological and mental effects of the disease itself. Therefore, and to increase the translational value of animal studies, the effects of irradiation should be studied together with cancer, in older animals, using varying irradiation protocols and doses. peerReviewed

Background: Millions of people live with depression and its burden of disease. Depression has an increased comorbidity and mortality that has remained unexplained. Studies have reported connections between advanced glycation end products (AGEs) and various disease processes, including mental health. The present study evaluated associations between AGEs, depressive symptoms, and types of depressive symptoms. Methods: From the Helsinki Birth Cohort Study, 815 participants with a mean age of 76 years were recruited for this cross-sectional study. Characteristics regarding self-reported lifestyle and medical history, as well as blood tests were obtained along with responses regarding depressive symptoms according to the Beck Depression Inventory (BDI) and Mental Health Inventory-5. Each participant had their AGE level measured non-invasively with skin autofluorescence (SAF). Statistical analyses looked at relationships between types of depressive symptoms and AGE levels by sex. Results: Of women, 27% scored >= 10 on the BDI and 18% of men, respectively. Men had higher crude AGE levels (mean [standard deviation], arbitrary units) (2.49 [0.51]) compared to women (2.33 [0.46]) (p < 0.001). The highest crude AGE levels were found in those with melancholic depressive symptoms (2.61 [0.57]), followed by those with non-melancholic depressive symptoms (2.45 [0.45]) and those with no depressive symptoms (2.38 [0.49]) (p = 0.013). These findings remained significant in the fully adjusted model. Conclusions: The current study shows an association between depressive symptoms and higher AGE levels. The association is likely part of a multi-factorial effect, and hence no directionality, causality, or effect can be inferred solely based on the results of this study.

Vitamin D is an essential micronutrient, playing a vital role in the regulation of calcium homeostasis and bone metabolism. In recent years, vitamin D has been increasingly recognized for its regulatory functions in immunomodulation, anti-inflammation, cellular proliferation and differentiation. The pandemic vitamin D deficiency has been associated with an increasing risk for several metabolic diseases. However, the effects of vitamin D deficiency and its supplementation on the underlying molecular mechanisms of these diseases are poorly understood. This thesis focuses on the effect of vitamin D on the regulation of molecular and metabolic signaling pathways involved in adipose tissue inflammation and hepatic insulin resistance. Study I examined the effect of vitamin D on the downregulation of inflammatory signaling pathways in adipose tissue. Vitamin D inhibited the translocation of the transcriptional factor NFκB as well as inhibiting the expression of inflammatory cytokines in human adipocytes differentiated from mesenchymal stromal cells (MSCs) and mature adipocytes isolated from intra-abdominal fat biopsies. In Study II, induction of vitamin D deficiency via a deficient diet impaired systemic glucose homeostasis and insulin sensitivity in lean and obese mice. Subsequent vitamin D re-supplementation restored the insulin sensitivity and ameliorated the hepatic tissue inflammation and oxidative stress in vitamin D deficient lean but not obese mice. In Study III, lower vitamin D levels were associated with a higher incidence of the metabolic syndrome in a cross-sectional cohort of older subjects living at latitude 65° North. In conclusion, vitamin D has an important role in modulating the molecular pathways involved in adipose tissue inflammation and insulin resistance in hepatic tissue. Adequate levels of vitamin D are necessary for the regulation of metabolic pathways to maintain body homeostasis. The generated data provide novel insights into the cellular mechanisms of vitamin D and represent a basis for oral vitamin D supplementation in the prevention of metabolic diseases. Tiivistelmä D-vitamiini on välttämätön mikroravinne, jolla on tärkeä tehtävä kalsiumin homeostaasin ja luun aineenvaihdunnan säätelyssä. Viime vuosina D-vitamiinin on todistettu osallistuvan yhä useampiin säätelytoimintoihin liittyen immuunivasteeseen, tulehduksen torjuntaan sekä solujen jakautumiseen ja erilaistumiseen. Maailmanlaajuisesti yleinen D-vitamiinin puutostila on yhdistetty useiden aineenvaihduntasairauksien kohonneeseen riskiin. D-vitamiinin puutoksen ja D-vitamiinilisän käytön vaikutusta näiden sairauksien molekyylimekanismeihin ei kuitenkaan tunneta vielä tarkemmin. Tämä opinnäytetyö keskittyy D-vitamiinin vaikutukseen rasvakudoksen tulehduksessa ja maksan insuliiniresistenssissä olevien molekyyli- ja metabolisten signalointireittien säätelyssä. Tutkimuksessa I tarkasteltiin D-vitamiinin vaikutusta rasvakudoksen tulehduksellisten signalointireittien hillitsemiseen. D-vitamiini inhiboi transkriptionaalisen tekijän NFκB:n siirtymistä ja tulehduksellisten sytokiinien ilmentymistä ihmisen mesenkymaalisista stroomasoluista (MSC) erilaistetuissa rasvasoluissa sekä sappirakkoleikkausten yhteydessä otetuista rasvanäytteistä eristetyissä kypsissä rasvasoluissa. Tutkimuksessa II havaittiin, että D-vitamiinin puutoksen aiheuttaminen puutteellisen ruokavalion avulla heikensi verenkierron glukoositasapainoa ja insuliiniherkkyyttä sekä hoikilla, että liikalihavilla hiirillä. Sitä vastoin D-vitamiini lisäravinteena palautti insuliiniherkkyyden ja lievitti maksakudoksen tulehdusta sekä oksidatiivista stressiä D-vitamiini puutteellisilla hoikilla hiirillä, mutta ei liikalihavilla hiirillä. Tutkimuksessa III selvisi, että kohortissa matalammat D-vitamiinitasot ovat yhteydessä suurempaan metabolisen oireyhtymän esiintyvyyteen iäkkäämmillä koehenkilöillä, jotka elävät pohjoisella pallonpuoliskolla (65° N). Yhteenvetona voidaan todeta, että D-vitamiinilla on tärkeä säätelevä rooli rasvakudostulehduksen ja insuliiniresistenssin molekyylireittien kontrolloinnissa maksakudoksessa. Riittävät D-vitamiinitasot ovat välttämättömiä aineenvaihduntareittien säätelyssä kehon homeostaasissa. Tutkimuksen tulokset tarjoavat uusia näkökulmia D-vitamiinin roolista solumekanismien säätelyssä ja perustan D-vitamiinilisien käytöstä aineenvaihduntasairauksissa.

Although gut bacterial dysbiosis is recognized as a regulator of beta-cell autoimmunity, no data is available on fungal dysbiosis in the children at the risk of type 1 diabetes (T1D). We hypothesized that the co-occurrence of fungal and bacterial dysbiosis contributes to the intestinal inflammation and autoimmune destruction of insulin-producing beta-cells in T1D. Fecal and blood samples were collected from 26 children tested positive for at least one diabetes-associated autoantibody (IAA, GADA, IA-2A or ICA) and matched autoantibody-negative children with HLA-conferred susceptibility to T1D (matched for HLA-DQB1 haplotype, age, gender and early childhood nutrition). Bacterial 16S and fungal ITS2 sequencing, and analyses of the markers of intestinal inflammation, namely fecal human beta-defensin-2 (HBD2), calprotectin and secretory total IgA, were performed. Anti-Saccharomyces cerevisiae antibodies (ASCA) and circulating cytokines, IFNG, IL-17 and IL-22, were studied. After these analyses, the children were followed for development of clinical T1D (median 8 years and 8 months). Nine autoantibody positive children were diagnosed with T1D, whereas none of the autoantibody negative children developed T1D during the follow-up. Fungal dysbiosis, characterized by high abundance of fecal Saccharomyces and Candida, was found in the progressors, i.e., children with beta-cell autoimmunity who during the follow-up progressed to clinical T1D. These children showed also bacterial dysbiosis, i.e., increased Bacteroidales and Clostridiales ratio, which was, however, found also in the non-progressors, and is thus a common nominator in the children with beta-cell autoimmunity. Furthermore, the progressors showed markers of intestinal inflammation detected as increased levels of fecal HBD2 and ASCA IgG to fungal antigens. We conclude that the fungal and bacterial dysbiosis, and intestinal inflammation are associated with the development of T1D in children with beta-cell autoimmunity.

Background Psychological processes can be manifested in physiological health. We investigated whether acceptance and commitment therapy (ACT), targeted on psychological flexibility (PF), influences inflammation and stress biomarkers among working-age adults with psychological distress and overweight/obesity. Method Participants were randomized into three parallel groups: (1) ACT-based face-to-face (n = 65; six group sessions led by a psychologist), (2) ACT-based mobile (n = 73; one group session and mobile app), and (3) control (n = 66; only the measurements). Systemic inflammation and stress markers were analyzed at baseline, at 10 weeks after the baseline (post-intervention), and at 36 weeks after the baseline (follow-up). General PF and weight-related PF were measured with questionnaires (Acceptance and Action Questionnaire, Acceptance and Action Questionnaire for Weight-Related Difficulties). Results A group × time interaction (p = .012) was detected in the high-sensitivity C-reactive protein (hsCRP) level but not in other inflammation and stress biomarkers. hsCRP decreased significantly in the face-to-face group from week 0 to week 36, and at week 36, hsCRP was lower among the participants in the face-to-face group than in the mobile group (p = .035, post hoc test). Age and sex were stronger predictors of biomarker levels at follow-up than the post-intervention PF. Conclusion The results suggest that ACT delivered in group sessions may exert beneficial effects on low-grade systemic inflammation. More research is needed on how to best apply psychological interventions for the health of both mind and body among people with overweight/obesity and psychological distress. Trial Registration ClinicalTrials.gov Identifier: NCT01738256, Registered 17 August, 2012

Purpose Studies have shown a positive influence of intense athletic training on several biomarkers of aging, but it remains unclear whether this influence is dependent of exercise-training-mode. This study compared redox balance, cytokine levels and biomarkers of aging between master sprinters and endurance athletes, as well as in young and middle-aged individuals as controls. Methods Participants were male master sprinters (SA, 50±8.9yrs; n=13) and endurance runners (EA, 53±8.2yrs; n=18) with remarkable athletic experience (∼25yrs of practice), besides untrained young (YC, 22.7±3.9yrs; n=17) and age-matched controls (MC, 45.5±9.8yrs; n=12). Anamnesis, anthropometrics, biomarkers of aging, inflammation status and oxidative stress parameters were analyzed in all participants. Results An increased pro-oxidant activity (elevated protein carbonyl; isoprostanes and 8-OHdG) was observed for MC in comparison to remaining groups (p

Purpose The aim of this study was to compare the efficacy of three water immersion interventions performed after active recovery compared to active recovery only on the resolution of inflammation and markers of muscle damage post-exercise. Methods Nine physically active men (n = 9; age 20‒35 years) performed an intensive loading protocol, including maximal jumps and sprinting on four occasions. After each trial, one of three recovery interventions (10 min duration) was used in a random order: cold-water immersion (CWI, 10 °C), thermoneutral water immersion (TWI, 24 °C), contrast water therapy (CWT, alternately 10 °C and 38 °C). All of these methods were performed after an active recovery (10 min bicycle ergometer), and were compared to active recovery only (ACT). 5 min, 1, 24, 48, and 96 h after exercise bouts, immune response and recovery were assessed through leukocyte subsets, monocyte chemoattractant protein-1, myoglobin and high-sensitivity C-reactive protein concentrations. Results Significant changes in all blood markers occurred at post-loading (p 0.5. Conclusions The recovery methods did not affect the resolution of inflammatory and immune responses after high-intensity sprinting and jumping exercise. It is notable that the biomarker responses were variable within individuals. Thus, the lack of differences between recovery methods may have been influenced by the reliability of exercise-induced biomarker responses. peerReviewed

Colorectal cancer (CRC) and cachexia are associated with the gut microbiota and microbial surface molecules. We characterized the CRC-associated microbiota and investigated whether cachexia affects the microbiota composition. Further, we examined the possible relationship between the microbial surface molecule flagellin and CRC. CRC cells (C26) were inoculated into mice. Activin receptor (ACVR) ligands were blocked, either before tumor formation or before and after, to increase muscle mass and prevent muscle loss. The effects of flagellin on C26-cells were studied in vitro. The occurrence of similar phenomena were studied in murine and human tumors. Cancer modulated the gut microbiota without consistent effects of blocking the ACVR ligands. However, continued treatment for muscle loss modified the association between microbiota and weight loss. Several abundant microbial taxa in cancer were flagellated. Exposure of C26-cells to flagellin increased IL6 and CCL2/MCP-1 mRNA and IL6 excretion. Murine C26 tumors expressed more IL6 and CCL2/MCP-1 mRNA than C26-cells, and human CRC tumors expressed more CCL2/MCP-1 than healthy colon sites. Additionally, flagellin decreased caspase-1 activity and the production of reactive oxygen species, and increased cytotoxicity in C26-cells. Conditioned media from flagellin-treated C26-cells deteriorated C2C12-myotubes and decreased their number. In conclusion, cancer increased flagellated microbes that may promote CRC survival and cachexia by inducing inflammatory proteins such as MCP-1. Cancer-associated gut microbiota could not be rescued by blocking ACVR ligands.

© 2018 Elsevier B.V. With increasing life expectancy, age-associated cognitive impairment is an escalating problem worldwide. Inflammation is one of the features that characterises cognitive decline and can stimulate neurodegeneration. Interleukin 6 (IL-6) is a cytokine frequently associated with a pro-inflammatory phenotype and increased levels have been associated with the pathogenesis of dementia. The rs1800796 polymorphism in the promoter region of IL-6 gene was previously shown to influence IL-6 expression and therefore we hypothesised this gene polymorphism would be associated with IL-6 plasma levels and cognitive performance of older adults. The present study investigated the association of the rs1800796 polymorphism on plasma IL-6 levels and cognition in healthy older adults (n = 207, 74.6 ± 3.4 years, 51% female) that participated in a Pan-European project (MyoAge). The participants were assessed for working memory capacity, executive functioning, episodic memory and global cognition using the Cambridge Neuropsychological Test Automated Battery CANTAB. Fasting plasma IL-6 levels were measured by ELISA and genotyping was performed using the KASP assay. Results showed that the rs1800796 polymorphism was in Hardy-Weinberg equilibrium (P =.16) with the minor allele (C) showing a frequency of 6.3%. There were no differences in plasma IL-6 concentrations between the GG-homozygotes and C-allele carriers (P =.22). The C-allele carriers performed worse on a measure of executive functioning (P =.035) and had lower global cognitive scores (P =.045), compared to GG-homozygotes. These differences remained significant after accounting for age, sex and prior cognitive abilities (P

Hypertension is the most common modifiable risk factor for cardiovascular disease (CVD)1 and is a leading cause of death globally.2 Hypertension and CVD share common antecedent risk factors which include physical inactivity, obesity and excess alcohol intake.3 Though these established risk factors explain a large proportion of hypertension risk, its pathogenesis is still not fully established as it appears that other additional lifestyle and genetic factors may be involved. There is therefore a need to identify and evaluate putative risk factors that may increase our knowledge of hypertension development, may have causal or predictive relevance, and which will help develop preventive and management strategies. nonPeerReviewed

Over the past 50 years, intentional genetic selection within the broiler industry has led to major improvements in both body weight gain (BWG) and feed conversion efficiency. Next to its economic advantages, enhancing BWG can increase the risk of metabolic and skeletal disorders. The aim of this study was to examine whether higher BWG is a predisposing factor for broiler necrotic enteritis. In this study, 300 broilers were challenged with Clostridium perfringens using a well-established, previously described challenge model. It was found that birds with higher body weight (BW) and BWG before challenge were predisposed to develop more severe necrotic enteritis lesions. After challenge, the average BWG of the birds developing mild to severe lesions dropped significantly, negatively affecting bird welfare and performance. These results show a significant interplay between BWG and the development of necrotic enteritis lesions. This raises the question whether there is a limit to broiler performance with respect to maintaining intestinal health, and whether decreasing BWG (at certain stages of the growth cycle) can be part of a plan to prevent intestinal pathology. peerReviewed

The main purpose of the present study was to investigate the effect of frequency, thereby increasing training volume, of resistance training on body composition, inflammation markers, lipid and glycemic profile in healthy older individuals (age range 65-75 year). Ninety-two healthy participants were randomly assigned to one of four groups; performing strength training one- (EX1), two- (EX2), or three- (EX3) times-per-week and a non-training control (CON) group. Whole-body strength training was performed using 2-5 sets and 4-12 repetitions per exercise and 7-9 exercises per session. All training groups attended supervised resistance training for 6 months. Body composition was measured by dual X-ray absorptiometry and fasting blood samples were taken pre- and post-training. There were significant main effects of time for total fat mass (F = 28.12, P < 0.001) and abdominal fat mass (F = 20.72, P < 0.001). Pre- to post-study, statistically significant reductions in fat mass (Delta = -1.3 +/- 1.4 kg, P < 0.001, n = 26) were observed in EX3. Pre- to post-study reductions in low density lipoprotein (LDL) concentration (Delta = -0.38 +/- 0.44 mmol.L-1 , P = 0.003, n = 19) were observed only in EX3, whereas a significant pre- to post-study increases in high density lipoprotein (HDL) concentration (0.14-0.19 mmol.L-1) were observed in all training groups. Most variables at baseline demonstrated a significant (negative) relationship when correlating baseline values with their change during the study including: Interleukin-6 (IL-6) (r = -0.583, P < 0.001), high-sensitivity c-reactive protein (hs-CRP) (r = -0.471, P < 0.001, and systolic blood pressure (r = -0.402, P = 0.003). The present study suggests that having more than two resistance training sessions in a week could be of benefit in the management of body composition and lipid profile. Nevertheless, interestingly, and importantly, those individuals with a higher baseline in systolic blood pressure, IL-6 and hs-CRP derived greatest benefit from the resistance training intervention, regardless of how many times-a-week they trained. Finally, the present study found no evidence that higher training frequency would induce greater benefit regarding inflammation markers or glycemic profile in healthy older adults.

We sought to determine cross-sectional and longitudinal associations of frequency of sauna bathing with high sensitivity C-reactive protein (hsCRP), fibrinogen, leucocyte count and gamma-glutamyltransferase (GGT).Baseline sauna bathing habits were assessed in 2269 men aged 42-61 years. Concentrations of hsCRP, fibrinogen, leucocyte count, and GGT were determined at baseline and 11 years later. The associations of sauna bathing frequency with baseline and 11-year hsCRP, fibrinogen, leucocyte count, and GGT levels were examined using robust multivariate regression analyses.In baseline analysis, 4-7 sauna sessions/week (compared with 1 sauna session/week) was associated with -0.84 mg/l (95% CI, -1.55, -0.14; p = .019) lower hsCRP; -0.07 g/l (95% CI, -0.15, 0.02; p = .112) lower fibrinogen; and -0.28 × 10Observational evidence supports the hypothesis that reduction in inflammation may be one of the pathways linking frequent sauna bathing with decreased risk of acute and chronic disease conditions. KEY MESSAGES Cross-sectional evidence or short-term studies suggest Finnish sauna bathing may exert its beneficial health effects via reduction in inflammation and oxidative stress; however, the long-term effects of sauna bathing on these outcomes are uncertain. In this population-based prospective cohort study, frequent sauna sessions significantly decreased levels of inflammatory markers at baseline and 11-year follow-up; but had no effect on oxidative stress. The health benefits of sauna bathing may in part be mediated via reduced systemic inflammation.

Vitamin D deficiency, obesity and short telomere length are reported to be associated with increased risk of metabolic diseases and all-cause mortality, through modulation of inflammatory pathways. The season of blood sampling, obesity and physical activity have been identified as determinants of 25-hydroxyvitamin D [25(OH)D], but their association with 25(OH)D2 (D2) and 25(OH)D3 (D3) is still poorly understood. In addition, relationships between 25(OH)D, body mass index (BMI), inflammation, and leukocyte telomere length (LTL) has not been previously established. A better understanding of the determinants, risk factors of vitamin D deficiency, and their relationship with BMI, inflammation, and LTL is needed. The study was based on the 31-year follow-up study of the Northern Finland Birth Cohort 1966 (N=4,758). Statistical analyses were used to 1) examine potential determinants of D2 and D3, and identify risk factors associated with hypovitaminosis D, 2) investigate the relationship of 25(OH)D and BMI with LTL and test whether it is independent of inflammatory pathways and, 3) assess how the association of BMI with inflammatory biomarkers might be mediated through 25(OH)D. Our results showed that D2 contributed 5% and D3 95% of the total 25(OH)D concentrations. When examined, the determinants for each isoform, periods of low sunlight exposure associated with increased D2, but with decreased D3. Oral contraceptives associated with increased concentrations of both. We confirmed the known risk factors of low vitamin D: low sunlight periods, residing in northern latitudes, and physical inactivity. Serum 25(OH)D was not an important determinant of LTL, and inflammation may partly mediate the BMI-LTL association. Higher serum 25(OH)D was inversely associated with inflammatory biomarkers, and the association between BMI and biomarkers was modestly mediated through lowered 25(OH)D. In conclusion, our results support the role of known risk factors in vitamin D deficiency and add information on specific determinants of D2 and D3. 25(OH)D did not associate with LTL in young adulthood. We have also provided new insights into a plausible role of vitamin D in BMI associated inflammation. An improved understanding of the role of vitamin D benefits public health in many ways (it can help prevent vitamin D deficiency by implementing lifestyle modification and supplementation). Tiivistelmä D-vitamiinin puutos, lihavuus ja lyhyt telomeerien pituus liittyvät mahdollisesti lisääntyneeseen riskiin sairastua metabolisiin sairauksiin sekä yleisemmin kuolleisuuteen. Eräs selitys tälle voi löytyä tulehdustekijöistä. Lihavuuden, liikunnan puutteen ja verinäytteenoton ajankohdan tiedetään vaikuttavan 25-hydroksi-D-vitamiinin [25(OH)D]-pitoisuuteen, mutta niiden yhteys D-vitamiinin isomuotoihin (D2, D3) on vielä huonosti tunnettu. Aiemmin ei ole selvitetty 25(OH)D:n, painoindeksin (BMI), tulehduksen ja leukosyyttien telomeerien pituuden (LTL) välisiä yhteyksiä, ja siksi näistä tarvitaan lisätutkimusta. Tutkimusaineistona oli Pohjois-Suomen 1966 syntymäkohortin, 31-vuoden seurantaan osallistuneet henkilöt (N=4,758). Tutkimuksessa keskityttiin 1) selvittämään D2- ja D3-vitamiinipitoisuuksien määrittäviä tekijöitä ja tunnistamaan D-vitamiinin puutteeseen liittyviä riskitekijöitä, 2) tutkimaan 25(OH)D-pitoisuuden ja BMI:n suhdetta LTL:n kanssa sekä testaamaan, onko suhde riippumaton tulehduksellisista tekijöistä ja 3) arvioimaan ilmeneekö BMI:n ja tulehdussytokiinien välinen yhteys 25(OH)D-pitoisuuden kautta. Tutkimus osoitti, että D2-isomuodon osuus oli 5 % ja D3:n osuus 95 % koko 25(OH)D-pitoisuudesta. Näitä isomuotoja määrittäviä tekijöitä tutkittaessa havaittiin, että vähäisellä auringonvalolle altistumisella on todennäköisesti yhteys lisääntyneeseen D2-pitoisuuteen, mutta alhaisempaan D3-pitoisuuteen. Suun kautta otettavien ehkäisypillereiden käytöllä oli yhteys molempien muotojen lisääntyneisiin pitoisuuksiin. Tutkimus vahvisti alhaisten D-vitamiinipitoisuuksien tunnetut riskitekijät: lyhyt altistus auringon valolle sekä fyysinen passiivisuus. 25(OH)D-pitoisuus ei ollut yhteydessä LTL:ään mutta tulehdus näytti osittain vaikuttavan BMI-LTL-assosiaatioon. Korkeampi 25(OH)D-pitoisuus yhdistyi matalampiin tulehdussytokiinipitoisuuksiin, kun taas matala 25(OH)D-pitoisuus muokkasi BMI:n ja biomarkkereiden välisisiä yhteyksiä, tosin heikosti. Yhteenvetona voidaan todeta, että tulokset tukevat tunnettujen riskitekijöiden merkitystä D-vitamiinin puutoksessa ja tuovat lisää tietoa eri isomuotoihin vaikuttavista tekijöistä. Tutkimus antaa myös uusia näkemyksiä D-vitamiinin roolista lihavuuteen liittyvässä matala-asteisessa tulehduksessa. D-vitamiinin vaikutuksien tarkempi tunteminen on merkityksellistä myös kansanterveyden kannalta.

Fatty liver (FL) disease is the most common type of chronic liver disease. We hypothesized that liver’s response to the process where large droplets of triglyceride fat accumulate in liver cells is reflected also in gene pathway expression in blood. Peripheral blood genome wide gene expression analysis and ultrasonic imaging of liver were performed for 1,650 participants (316 individuals with FL and 1,334 controls) of the Young Finns Study. Gene set enrichment analysis (GSEA) was performed for the expression data. Fourteen gene sets were upregulated (false discovery rate, FDR

Ihmisen vanhetessa eri elinjärjestelmien, kuten rasvakudoksen ja immuunijärjestelmän, toiminta häiriintyy, minkä seurauksena ihminen riski sairastua moniin sairauksiin kasvaa. Vanhenemista tapahtuu myös molekyylitasolla, sillä DNA:ssa tapahtuu vanhetessa epigeneettisiä muutoksia. Elinikä on osittain perinnöllistä ja pitkäikäisten ihmisten jälkeläiset sairastuvat vanhuuteen liittyviin sairauksiin myöhemmin. Tässä tutkimuksessa pyrittiin selvittämään, miten isovanhempien elinikä vaikuttaa jälkeläisten vanhenemiseen mittaamalla ja vertaamalla jälkeläisten rasvakudoksen, rasva-aineenvaihdunnan, immuunijärjestelmän ja DNA:n vanhenemismuutoksia. Aineistona käytettiin Lasten Sepelvaltimotautien Riskitekijät -tutkimuksessa kerättyä aineistoa (n = 3 596), jota on kerätty eri puolilta Suomea vuodesta 1980 alkaen. Selvitettiin, miten tapausten isovanhempien eliniän pituus vaikuttaa tapausten rasvakoostumukseen, rasva-arvoihin, tulehdusarvoihin ja DNA-metylaatioikään, sillä näiden muuttujien arvojen suuruus on yhteydessä yksilön ikään. Analyysi tehtiin jakamalla tapaukset isovanhempien eliniän perusteella 55–74 vuotta ja yli 75 vuotta eläneiden isovanhempien lapsenlapsiin. Näissä ryhmissä verrattiin keskiarvoja ja mediaaneja kunkin muuttujan osalta. Muuttujille, joissa oli eroja ryhmien välillä, tehtiin joko kahden riippumattoman otoksen t-testi ja Mann-Whitney U-testi. Selvisi, että isovanhempien yli 75 vuoden elinikä on yhteydessä naispuolisten lastenlasten alhaisempaan BMI:hin (1,7 BMI yksikköä alhaisempi), rasvaprosenttiin (5,4 prosenttiyksikköä alhaisempi) ja miespuolisten lastenlasten alhaisempiin triglyserideihin (0,21 mmol/l alhaisempi). Näihin tuloksiin vaikuttavat vanhenemisen ohella monet muutkin tekijät, kuten lihavuuteen vaikuttavat geenit, elämäntavat ja sosioekonominen asema. Muiden vanhenemismuutoksia kuvaavien muuttujien ja isovanhempien eliniän välillä ei kuitenkaan ollut merkitseviä yhteyksiä, joten isovanhempien eliniän vaikutuksesta nimenomaan jälkeläisten vanhenemiseen ei voitu tehdä johtopäätöksiä.

The aim of the present dissertation was to examine the acute and chronic effects of resistance exercise on inflammation markers in young men. In addition, the effect of combined resistance and endurance training on inflammation was assessed. The present dissertation consisted of four studies. Acute inflammation response was evaluated using cross-sectional design after hypertrophic and maximal (n=12) resistance exercise bouts (I). In addition, acute inflammation was examined before and after resistance training (RT) consisting either hypertrophic or maximal explosive (n=8) resistance exercise bouts (RE) (II). The effect of RT on basal levels of markers of systemic inflammation was evaluated after an initial phase RT after which the participants were randomly assigned to hypertrophy-strength training (n=37) or to hypertrophy-strength-power training (n=31) (III). Additionally, the effect of combined training (resistance and endurance) was evaluated after 24 weeks of training (n=48) (IV). Hypertrophic RE led to greater acute responses in inflammation markers compared to maximal strength RE (I). An enhanced MCP-1 response was observed during the recovery phase after RT in hypertrophic resistance exercise along with acute enhanced IL-1ra and reduced IL-1ǃ response. Thus, high-intensity RT modifies the RE-induced cytokine responses. Both training studies (III, IV) led to significantly improved lean mass and maximal strength as well as reduced abdominal fat mass. In the RT study (III), the initial four week phase of RT lead to increased circulating resistin, MCP-1, and IL-1ra concentrations, and decreased circulating leptin concentration. After the specialized RT periods, hypertrophy-strength RT elicited normalizing effects on inflammation markers, such as circulating resistin and leptin, whereas hypertrophy-strength-power did not have an effect on these markers. Combined training (IV) reduces concentrations of C-reactive protein, leptin, and resistin, and when performed on alternating days elicited the largest reductions in abdominal fat mass as well as circulating levels of TNF-ǂ and MCP-1. The findings of the present dissertation suggest that the beneficial effects of resistance training could be due to the repeated effect of one bout of resistance exercise on inflammation markers as well as the favorable changes in body composition following RT