In vitro human metabolism and inhibition potency of verbascoside for CYP enzymes

Verbascoside is found in many medicinal plant families such as Verbenaceae. Important biological activities have been ascribed to verbascoside. Investigated in this study is the potential of verbascoside as an adjuvant during tuberculosis treatment. The present study reports on the in vitro metabolism in human hepatic microsomes and cytosol incubations as well as the presence and quantity of verbascoside within Lippia scaberrima. Additionally, studied are the inhibitory properties on human hepatic CYP enzymes together with antioxidant and cytotoxic properties. The results yielded no metabolites in the hydrolysis or cytochrome P450 (CYP) oxidation incubations. However, five different methylated conjugates of verbascoside could be found in S-adenosylmethionine incubation, three different sulphate conjugates with 30 -phosphoadenosine 50 -phosphosulfate (PAPS) incubation with human liver samples, and very low levels of glucuronide metabolites after incubation with recombinant human uridine 5’-diphospho-glucuronosyltransferase (UGT) 1A7, UGT1A8, and UGT1A10. Additionally, verbascoside showed weak inhibitory potency against CYP1A2 and CYP1B1 with IC50 values of 83 µM and 86 µM, respectively. Potent antioxidant and low cytotoxic potential were observed. Based on these data, verbascoside does not possess any clinically relevant CYP-mediated interaction potential, but it has effective biological activity. Therefore, verbascoside could be considered as a lead compound for further drug development and as an adjuvant during tuberculosis treatment.National Research Foundationhttps://www.mdpi.com/journal/moleculespm2020Plant Production and Soil Scienc

Structure-Activity Relationship Analysis of 3-Phenylcoumarin-Based Monoamine Oxidase B Inhibitors

Monoamine oxidase B (MAO-B) catalyzes deamination of monoamines such as neurotransmitters dopamine and norepinephrine. Accordingly, small-molecule MAO-B inhibitors potentially alleviate the symptoms of dopamine-linked neuropathologies such as depression or Parkinson's disease. Coumarin with a functionalized 3-phenyl ring system is a promising scaffold for building potent MAO-B inhibitors. Here, a vast set of 3-phenylcoumarin derivatives was designed using virtual combinatorial chemistry or rationally de novo and synthesized using microwave chemistry. The derivatives inhibited the MAO-B at 100 nM-1 mu M. The IC50 value of the most potent derivative 1 was 56 nM. A docking-based structure-activity relationship analysis summarizes the atom-level determinants of the MAO-B inhibition by the derivatives. Finally, the cross-reactivity of the derivatives was tested against monoamine oxidase A and a specific subset of enzymes linked to estradiol metabolism, known to have coumarin-based inhibitors. Overall, the results indicate that the 3-phenylcoumarins, especially derivative 1, present unique pharmacological features worth considering in future drug development

Biomarkers of effect as determined in human biomonitoring studies on hexavalent chromium and cadmium in the period 2008–2020

This research was supported by funding from the European Union's Horizon 2020 research and innovation Programme under grant agreement No 733032 HBM4EU.A number of human biomonitoring (HBM) studies have presented data on exposure to hexavalent chromium [Cr (VI)] and cadmium (Cd), but comparatively few include results on effect biomarkers. The latter are needed to identify associations between exposure and adverse outcomes (AOs) in order to assess public health implications. To support improved derivation of EU regulation and policy making, it is of great importance to identify the most reliable effect biomarkers for these heavy metals that can be used in HBM studies. In the framework of the Human Biomonitoring for Europe (HBM4EU) initiative, our study aim was to identify effect biomarkers linking Cr(VI) and Cd exposure to selected AOs including cancer, immunotoxicity, oxidative stress, and omics/epigenetics. A comprehensive PubMed search identified recent HBM studies, in which effect biomarkers were examined. Validity and applicability of the markers in HBM studies are discussed. The most frequently analysed effect biomarkers regarding Cr(VI) exposure and its association with cancer were those indicating oxidative stress (e.g., 8-hydroxy-2 & rsquo;-deoxyguanosine (8-OHdG), malondialdehyde (MDA), glutathione (GSH)) and DNA or chromosomal damage (comet and micronucleus assays). With respect to Cd and to some extent Cr, 0-2-microglobulin (B2-MG) and N-acetyl-0-D-glucosaminidase (NAG) are well-established, sensitive, and the most common effect biomarkers to relate Cd or Cr exposure to renal tubular dysfunction. Neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule (KIM)-1 could serve as sensitive biomarkers of acute kidney injury in response to both metals, but need further investigation in HBM studies. Omics-based biomarkers, i.e., changes in the (epi-)genome, transcriptome, proteome, and metabolome associated with Cr and/or Cd exposure, are promising effect biomarkers, but more HBM data are needed to confirm their significance. The combination of established effect markers and omics biomarkers may represent the strongest approach, especially if based on knowledge of mechanistic principles. To this aim, also mechanistic data were collected to provide guidance on the use of more sensitive and specific effect biomarkers. This also led to the identification of knowledge gaps relevant to the direction of future research.European Commission 733032 HBM4E

Kuopio birth cohort - design of a Finnish joint research effort for identification of environmental and lifestyle risk factors for the wellbeing of the mother and the newborn child

Background: A Finnish joint research effort Kuopio Birth Cohort (KuBiCo) seeks to evaluate the effects of genetics, epigenetics and different risk factors (medication, nutrition, lifestyle factors and environmental aspects) during pregnancy on the somatic and psychological health status of the mother and the child. Methods: KuBiCo will ultimately include information on 10,000 mother-child pairs who have given their informed consent to participate in this cohort. Identification of foetal health risk factors that can potentially later manifest as disease requires a repository of relevant biological samples and a flexible open up-to-date data handling system to register, store and analyse biological, clinical and questionnaire-based data. KuBiCo includes coded questionnaire-based maternal background data gathered before, during and after the pregnancy and bio-banking of maternal and foetal samples that will be stored in deep freezers. Data from the questionnaires and biological samples will be collected into one electronic database. KuBiCo consists of several work packages which are complementary to each other: Maternal, foetal and placental metabolism and omits; Paediatrics; Mental wellbeing; Prenatal period and delivery; Analgesics and anaesthetics during peripartum period; Environmental effects; Nutrition; and Research ethics. Discussion: This report describes the set-up of the KuBiCo and descriptive analysis from 3532 parturients on response frequencies and feedback to KuBiCo questionnaires gathered from June 2012 to April 2016. Additionally, we describe basic demographic data of the participants (n = 1172). Based on the comparison of demographic data between official national statistics and our descriptive analysis, KuBiCo represents a cross-section of Finnish pregnant women.Peer reviewe

Maankäyttösektorin ilmastotoimenpiteet: Arvio päästövähennysmahdollisuuksista

Maankäyttösektorin ilmastotoimet – arvio päästövähennysmahdollisuuksista Hallitusohjelman (2019) mukaisia maankäyttösektorin ilmastotoimenpiteitä valmistellaan sisällytettäväksi vuonna 2021 laadittavaan maankäyttösektorin ilmastosuunnitelmaan. Valmistelun tueksi tarvitaan tietoa keinoista, joilla maankäyttösektorin päästöjä voidaan vähentää, hiilivarastoja ylläpitää ja hiilinieluja vahvistaa, sekä arvioita potentiaalisten toimenpiteiden vaikutuksista lyhyellä ja pitkällä aikavälillä. Tässä tutkimuksessa on arvioitu maankäyttösektorin ilmastotoimenpiteiden vaikutuksia nykyistä tutkimustietoa ja asiantuntija-arvioita kokoamalla sekä valmiina käytettävissä olevia mallinnusmenetelmiä soveltaen. Toimenpiteiden päästövähennys ja hiilinieluvaikutuksien arvioinnissa käytettiin kunkin toimenpiteen kohdalla parasta käytettävissä olevaa menetelmää ja toimenpiteen soveltamismahdollisuuksien laajuus perustui asiantuntija-arvioihin. Tuloksiin liittyy sekä sovelletusta menetelmästä ja siinä käytettävistä tiedoista että toimenpiteen laajuuden arvioinnista johtuvaa epävarmuutta. Tutkimus sisältää myös laadulliset arviot ilmastotoimenpiteiden vaikutuksista muihin ekosysteemipalveluihin, vesistökuormitukseen ja luonnon monimuotoisuuteen. Lisäksi on tunnistettu vaikuttavuusarvioinnin kannalta merkittäviä kehittämis- ja tutkimustarpeita sekä tietoaukkoja. Tulokset auttavat kohdentamaan ilmastotoimenpiteet vaikutuksiltaan merkittävimpiin, joilla tuetaan Suomen tavoitetta saavuttaa hiilineutraalius vuoteen 2035 mennessä. Maankäyttösektorilla on monia mahdollisuuksia vahvistaa hiilinieluja, ylläpitää hiilivarastoja ja vähentää kasvihuonekaasupäästöjä. Kaikkien tunnistettujen ilmastotoimenpiteiden toteuttaminen tutkimuksessa oletetussa laajuudessa vaatisi erittäin laajoja muutoksia maankäyttösektorin ohjauskeinoissa, investointeja päästöjä vähentäviin ja nieluja lisääviin toimenpiteisiin sekä mm. puutuotteiden osalta muutoksia myös maankäyttösektorin ulkopuolella metsäteollisuuden tuotantorakenteessa. Potentiaalisesti suurimmat päästövähennykset voidaan saavuttaa muuttamalla turvemaapeltojen viljelykäytäntöjä ja jatkamalla runsasravinteisissa ojitetuissa turvemaametsissä metsänkasvatusta avohakkuiden sijaan harvennuksin ja ilman kunnostusojituksia. Turvemaapeltojen käsittelyä muuttamalla saadaan suhteellisen pienellä pinta-alalla aikaan merkittäviä päästösäästöjä hidastamalla turpeen hiilivaraston purkautumista, kun kivennäismaapeltojen vaikuttavat ilmastotoimet vaatisivat vuosittaista lisätukea lähes koko käytössä olevalle peltopinta-alalle. Osa tunnistetuista ilmastotoimenpiteistä on pitkävaikutteisia, esimerkiksi suometsässä kerran tehdyn puutuhkalannoituksen puuston hiilinielua vahvistava vaikutus kestää kymmeniä vuosia. Metsien hiilinielua kasvattaisivat merkittävästi myös uusien suojelualueiden perustaminen, säästöpuumäärän lisääminen ja metsäteollisuuden tuotantorakenteen muutos, joka kasvattaisi pitkäikäisten puutuotteiden osuutta. Maankäyttösektorin monilla ilmastotoimenpiteillä edistetään myös luonnon monimuotoisuuden säilymistä ja vähennetään maa- ja metsätalouden haitallisia ympäristövaikutuksia. Erityisesti turvemaiden viljely- ja metsänkasvatusmenetelmiä uudistamalla saadaan tavoitellun ilmastovaikutuksen ohella vähennettyä vesistökuormitusta. Monimuotoisuuden säilyttämistä tukisivat erityisesti suojelualueiden lisääminen, jota oletimme jatkettavan METSO-ohjelmassa toteutuneessa laajuudessa, ja säästöpuiden määrän kaksinkertaistaminen mikä lisäisi lahopuun hiilivarastoa talousmetsissä. Kivennäismaapeltojen maaperän hoito, metsänlannoitus ja turvemaametsien maaperän päästövähennystoimet voivat edistää myös tuotannon taloudellista kannattavuutta. Nykyiset maa- ja metsätalouden tuet eivät kannusta kaikkien potentiaalisesti merkittävimpien päästöjä vähentävien ilmastotoimenpiteiden käyttöönottoon. Maankäyttösektorin ilmastotoimenpiteiden kustannustehokkuuden ja sosiaalisen hyväksyttävyyden tutkimus on rajattu tämän tutkimuksen ulkopuolelle. Näiden tarkastelu jatkotutkimuksissa on välttämätöntä, jotta toimenpiteet osataan suunnata kustannustehokkaasti ja siten että maanomistajilla on mahdollisuus ja kannusteet niitä toteuttaa. Ilmastotoimenpiteiden vaikutuksia puuntuotannon ja viljelyn taloudelliseen kannattavuuteen, muihin ekosysteemipalveluihin ja biodiversiteettiin tarkasteltiin vain laadullisesti tutkimuskirjallisuuden ja asiantuntija-arvioiden perusteella. Näiden laajempi määrällinen tarkastelu edellyttäisi lisätutkimusta ja myös laskentatyökalujen ja mallien kehitystyötä. Ilmastotoimenpiteiden vaikuttavuusarvioon liittyy paljon epävarmuuksia. Arvioita on perusteltua tarkentaa, kun tutkimustietoa kertyy lisää ja laskentamenetelmät kehittyvät

Maa- ja metsätalouden sekä koko maankäyttösektorin ilmastotoimenpiteillä on suuret päästövähennysmahdollisuudet

Suomen tavoitteena on olla hiilineutraali vuonna 2035. Tavoitetta ei voi saavuttaa ilman maankäyttösektorin hiilinieluja. Suomen kokonaispäästöt olivat vuonna 2019 yhteensä 53,1 Mt CO2 ekv. ja maankäyttösektorin nettonielut 14,7 Mt CO2 ekv. Hiilineutraaliustavoitteen saavuttamiseen tarvitaan kaikilta sektoreilta päästövähennyksiä tai lisänieluja. Tässä politiikkasuosituksessa esitellään ilmastopoliittisen päätöksenteon tueksi keinoja päästövähennysten saavuttamiseksi sekä arvioita maankäyttösektorin päästöjä vähentävien ja nieluja vahvistavien toimenpiteiden potentiaalisista vaikutuksista (Lehtonen ym. 2021)

EU-wide exposure data of 11 chemical substance groups from the HBM4EU Aligned Studies (2014–2021)

Funding Information: The authors would like to thank everybody who contributed to the HBM4EU Aligned Studies: the participating children, teenagers, adults and their families, the fieldworkers that collected the samples and database managers that made the information available to HBM4EU, the HBM4EU project partners, especially those from WP7 for developing all materials supporting the fieldwork, WP9 for organizing the QA/QC scheme under HBM4EU and all laboratories who performed the analytical measurements. We would like to acknowledge Sun Kyoung Jung from the National Institute of Environmental Research of South-Korea for providing the KoNEHS Cycle III results (crt adjusted). HBM4EU is co-financed under Horizon 2020 (grant agreement No 733032). The authors thank all principal investigators of the contributing studies for their participation and contribution to the HBM4EU Aligned Studies and the national program owners for their financial support. Further details on funding for all the participating studies can be found in the Supplemental Material, Table S12.As one of the core elements of the European Human Biomonitoring Initiative (HBM4EU) a human biomonitoring (HBM) survey was conducted in 23 countries to generate EU-wide comparable HBM data. This survey has built on existing HBM capacity in Europe by aligning national or regional HBM studies, referred to as the HBM4EU Aligned Studies. The HBM4EU Aligned Studies included a total of 10,795 participants of three age groups: (i) 3,576 children aged 6–12 years, (ii) 3,117 teenagers aged 12–18 years and (iii) 4,102 young adults aged 20–39 years. The participants were recruited between 2014 and 2021 in 11–12 countries per age group, geographically distributed across Europe. Depending on the age group, internal exposure to phthalates and the substitute DINCH, halogenated and organophosphorus flame retardants, per- and polyfluoroalkyl substances (PFASs), cadmium, bisphenols, polycyclic aromatic hydrocarbons (PAHs), arsenic species, acrylamide, mycotoxins (deoxynivalenol (total DON)), benzophenones and selected pesticides was assessed by measuring substance specific biomarkers subjected to stringent quality control programs for chemical analysis. For substance groups analyzed in different age groups higher average exposure levels were observed in the youngest age group, i.e., phthalates/DINCH in children versus teenagers, acrylamide and pesticides in children versus adults, benzophenones in teenagers versus adults. Many biomarkers in teenagers and adults varied significantly according to educational attainment, with higher exposure levels of bisphenols, phthalates, benzophenones, PAHs and acrylamide in participants (from households) with lower educational attainment, while teenagers from households with higher educational attainment have higher exposure levels for PFASs and arsenic. In children, a social gradient was only observed for the non-specific pyrethroid metabolite 3-PBA and di-isodecyl phthalate (DiDP), with higher levels in children from households with higher educational attainment. Geographical variations were seen for all exposure biomarkers. For 15 biomarkers, the available health-based HBM guidance values were exceeded with highest exceedance rates for toxicologically relevant arsenic in teenagers (40%), 3-PBA in children (36%), and between 11 and 14% for total DON, Σ (PFOA + PFNA + PFHxS + PFOS), bisphenol S and cadmium. The infrastructure and harmonized approach succeeded in obtaining comparable European wide internal exposure data for a prioritized set of 11 chemical groups. These data serve as a reference for comparison at the global level, provide a baseline to compare the efficacy of the European Commission's chemical strategy for sustainability and will give leverage to national policy makers for the implementation of targeted measures.publishersversionpublishe

Harmonized human biomonitoring in European children, teenagers and adults: EU-wide exposure data of 11 chemical substance groups from the HBM4EU Aligned Studies (2014–2021)

HBM4EU is co-financed under Horizon 2020 (grant agreement No 733032).As one of the core elements of the European Human Biomonitoring Initiative (HBM4EU) a human biomonitoring (HBM) survey was conducted in 23 countries to generate EU-wide comparable HBM data. This survey has built on existing HBM capacity in Europe by aligning national or regional HBM studies, referred to as the HBM4EU Aligned Studies. The HBM4EU Aligned Studies included a total of 10,795 participants from three age groups: (i) 3,576 children aged 6-12 years, (ii) 3,117 teenagers aged 12-18 years, and (iii) 4,102 young adults aged 20-39 years. The participants were recruited between 2014 and 2021 in 11-12 countries per age group, geographically distributed across Europe. Depending on the age group, internal exposure to phthalates and the substitute DINCH, halogenated and organophosphorus flame retardants, per- and polyfluoroalkyl substances (PFASs), cadmium, bisphenols, polycyclic aromatic hydrocarbons (PAHs), arsenic species, acrylamide, mycotoxins (deoxynivalenol (total DON)), benzophenones and selected pesticides was assessed by measuring substance specific biomarkers subjected to stringent quality control programs for chemical analysis. For substance groups analyzed in different age groups higher average exposure levels were observed in the youngest age group, i.e., phthalates/DINCH in children versus teenagers, acrylamide and pesticides in children versus adults, and benzophenones in teenagers versus adults. Many biomarkers in teenagers and adults varied significantly according to educational attainment, with higher exposure levels of bisphenols, phthalates, benzophenones, PAHs, and acrylamide in participants (from households) with lower educational attainment, while teenagers from households with higher educational attainment have higher exposure levels for PFASs and arsenic. In children, a social gradient was only observed for the non-specific pyrethroid metabolite 3-PBA and di-isodecyl phthalate (DiDP), with higher levels in children from households with higher educational attainment. Geographical variations were seen for all exposure biomarkers. For 15 biomarkers, the available health-based HBM guidance values were exceeded with the highest exceedance rates for toxicologically relevant arsenic in teenagers (40%), 3-PBA in children (36%), and between 11 and 14% for total DON, Σ (PFOA + PFNA + PFHxS + PFOS), bisphenol S and cadmium. The infrastructure and harmonized approach succeeded in obtaining comparable European-wide internal exposure data for a prioritized set of 11 chemical groups. These data serve as a reference for comparison at the global level, provide a baseline to compare the efficacy of the European Commission's chemical strategy for sustainability, and will give leverage to national policymakers for the implementation of targeted measures.info:eu-repo/semantics/publishedVersio

Harmonized human biomonitoring in European children, teenagers and adults : EU-wide exposure data of 11 chemical substance groups from the HBM4EU Aligned Studies (2014–2021)

Funding Information: The authors would like to thank everybody who contributed to the HBM4EU Aligned Studies: the participating children, teenagers, adults and their families, the fieldworkers that collected the samples and database managers that made the information available to HBM4EU, the HBM4EU project partners, especially those from WP7 for developing all materials supporting the fieldwork, WP9 for organizing the QA/QC scheme under HBM4EU and all laboratories who performed the analytical measurements. We would like to acknowledge Sun Kyoung Jung from the National Institute of Environmental Research of South-Korea for providing the KoNEHS Cycle III results (crt adjusted). HBM4EU is co-financed under Horizon 2020 (grant agreement No 733032). The authors thank all principal investigators of the contributing studies for their participation and contribution to the HBM4EU Aligned Studies and the national program owners for their financial support. Further details on funding for all the participating studies can be found in the Supplemental Material, Table S12. Funding Information: The authors would like to thank everybody who contributed to the HBM4EU Aligned Studies: the participating children, teenagers, adults and their families, the fieldworkers that collected the samples and database managers that made the information available to HBM4EU, the HBM4EU project partners, especially those from WP7 for developing all materials supporting the fieldwork, WP9 for organizing the QA/QC scheme under HBM4EU and all laboratories who performed the analytical measurements. We would like to acknowledge Sun Kyoung Jung from the National Institute of Environmental Research of South-Korea for providing the KoNEHS Cycle III results (crt adjusted). HBM4EU is co-financed under Horizon 2020 (grant agreement No 733032). The authors thank all principal investigators of the contributing studies for their participation and contribution to the HBM4EU Aligned Studies and the national program owners for their financial support. Further details on funding for all the participating studies can be found in the Supplemental Material, Table S12 . Publisher Copyright: © 2023 The AuthorsAs one of the core elements of the European Human Biomonitoring Initiative (HBM4EU) a human biomonitoring (HBM) survey was conducted in 23 countries to generate EU-wide comparable HBM data. This survey has built on existing HBM capacity in Europe by aligning national or regional HBM studies, referred to as the HBM4EU Aligned Studies. The HBM4EU Aligned Studies included a total of 10,795 participants of three age groups: (i) 3,576 children aged 6–12 years, (ii) 3,117 teenagers aged 12–18 years and (iii) 4,102 young adults aged 20–39 years. The participants were recruited between 2014 and 2021 in 11–12 countries per age group, geographically distributed across Europe. Depending on the age group, internal exposure to phthalates and the substitute DINCH, halogenated and organophosphorus flame retardants, per- and polyfluoroalkyl substances (PFASs), cadmium, bisphenols, polycyclic aromatic hydrocarbons (PAHs), arsenic species, acrylamide, mycotoxins (deoxynivalenol (total DON)), benzophenones and selected pesticides was assessed by measuring substance specific biomarkers subjected to stringent quality control programs for chemical analysis. For substance groups analyzed in different age groups higher average exposure levels were observed in the youngest age group, i.e., phthalates/DINCH in children versus teenagers, acrylamide and pesticides in children versus adults, benzophenones in teenagers versus adults. Many biomarkers in teenagers and adults varied significantly according to educational attainment, with higher exposure levels of bisphenols, phthalates, benzophenones, PAHs and acrylamide in participants (from households) with lower educational attainment, while teenagers from households with higher educational attainment have higher exposure levels for PFASs and arsenic. In children, a social gradient was only observed for the non-specific pyrethroid metabolite 3-PBA and di-isodecyl phthalate (DiDP), with higher levels in children from households with higher educational attainment. Geographical variations were seen for all exposure biomarkers. For 15 biomarkers, the available health-based HBM guidance values were exceeded with highest exceedance rates for toxicologically relevant arsenic in teenagers (40%), 3-PBA in children (36%), and between 11 and 14% for total DON, Σ (PFOA + PFNA + PFHxS + PFOS), bisphenol S and cadmium. The infrastructure and harmonized approach succeeded in obtaining comparable European wide internal exposure data for a prioritized set of 11 chemical groups. These data serve as a reference for comparison at the global level, provide a baseline to compare the efficacy of the European Commission's chemical strategy for sustainability and will give leverage to national policy makers for the implementation of targeted measures.Peer reviewe