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Phytoncides (Wood Essential Oils) Induce Human Natural Killer Cell Activity
Abstract
To explore the effect of forest bathing on the human immune system, we investigated the effect of phytoncides (wood essential oils) on natural killer (NK) activity and the expression of perforin, granzyme A and granulysin in human NK cells. We used NK-92MI cell, an interleukin-2 independent human NK cell line derived from the NK-92 cell, in the present study. NK-92MI cells express the CD56 surface marker, perforin, granzyme A, and granulysin by flow cytometry and are highly cytotoxic to K562 cells in chromium release assay. Phytoncides significantly increase cytolytic activity of NK-92MI cells in a dose-dependent manner and significantly increase the expression of perforin, granzyme A, and granulysin in the NK-92MI cells. Phytoncides also partially, but significantly, restore the decreased human NK activity and the decreased perforin, granzyme A, and granulysin expression in NK-92MI cells induced by dimethyl 2,2-dichlorovinyl phosphate (DDVP), an organophosphorus pesticide. Pretreatment with phytoncides partially prevents DDVP-induced inhibition of NK activity. Taken together, these data indicate that phytoncides significantly enhance human NK activity and this effect is at least partially mediated by induction of intracellular perforin, granzyme A, and granulysin.
... While most research has focused on the visual aspect of nature contact, a few studies have looked at the role of sound (Diette, Lechtzin, Haponik, Devrotes, & Rubin, 2003;Kline, 2009); scent (Li et al., 2006(Li et al., , 2007(Li et al., , 2008Oka, et al., 2008) and even ingestion or inhalation of beneficial bacteria found in soil (Matthews, 2010;Lowry et al., 2007). Some studies have also focused on the benefits of active interaction with nature, particularly gardening and horticultural therapy (Hayashi et al., 2008;Sato, Metoki, Iwamoto, & Satoh, 2003;Turner, Bass, Ting, & Brown, 2002;Wichrowski, Whiteson, Haas, Mola, & Rey, 2005;Wang & MacMillan, 2013). ...
... Outcomes. The most frequently documented positive outcomes involve reduction in stress, anxiety, and depression (e.g., Berman, Jonides, & Kaplan, 2008;Bratman, Hamilton, Hahn, Daily, & Gross, 2015;Gray, 2011;Heerwagen & Orians, 1986;Kaplan & Kaplan, 1989;Li et al., 2006Li et al., , 2007Li et al., , 2008Ward Thompson et al., 2012). A systematic review in 2010 by Bowler and colleagues found greater positive effects from green natural environments when compared with built environments as related to anger, depression, mental fatigue, energy, and attention. ...
... Phytoncides: Trees give off phytoncides, antimicrobial volatile organic compounds (wood essential oils) that have been found to reduce blood pressure and boost immune function, including stimulating the production of NK cells-natural killer cells that fight cancer cells (Dayawansa et al., 2003;Komori, Fujiwara, Tanida, Nomura, & Yokoyama, 1995;Li et al., 2006Li et al., , 2007Li et al., , 2008. The greater the density of trees, the higher the concentration phytoncides. ...
As healthcare organizations and designers accept, and even embrace, healing gardens and other natural spaces as modalities for promoting the health and well-being of patients, visitors, and staff, the spaces provided must be designed and programmed to best optimize user health outcomes. Valid, reliable research instruments can aid in the evaluation of existing spaces. They can also be used as guides and tools for future design and research. The Healthcare Garden Evaluation Toolkit (H-GET) is a set of four standardized instruments developed for use, individually or in combination, by researchers, designers, and healthcare providers to evaluate, design, and research gardens in general acute care hospitals. Evaluation is an important component of research on the designed environment, and is a critical part of evidence-based design. The more valid and reliable the instrument, the greater the likelihood that results will be credible and generalizable. To date, despite a clear need, there are no rigorously tested, validated instruments available for the evaluation of outdoor spaces in general acute care hospitals. The H-GET fills this need. This mixed methods study involved development and testing of the four H-GET instruments: (a) the Garden Assessment Tool for Evaluators; (b) Staff and Patient/Visitor Surveys; (c) Behavior Mapping protocol ; and (d) Stakeholder Interviews. All four instruments were tested at eight Pilot Test sites across the United States. Emphasis with data collection and analysis was on establishing instrument reliability and validity. Data from each instrument were analyzed, and data from the four instruments were triangulated to examine support for validity and to explore specific hypotheses about physical and programmatic factors that promote garden use and user satisfaction. Through H-GET pilot testing, a Healthcare Garden Evaluation Method (HGEM) emerged—a methodological process that the individual instruments facilitate in a rigorous, standardized, research-based format for future studies’ design, protocol, data collection, data analysis, and dissemination of findings.
... It is the total effect from all five senses: senses of sight, smell, hearing, touch and taste. In fact, sense of smell by breathing in volatile organic substances, called phytoncides from trees, such as ¡-pinene and limonene has a bigger effect [27,59]. My research team found that phytoncides released from trees significantly increased human NK activity and the intracellular levels of perforin, GrA, and GRN in human NK cells both in vitro [59] and in vivo [27]. ...
... In fact, sense of smell by breathing in volatile organic substances, called phytoncides from trees, such as ¡-pinene and limonene has a bigger effect [27,59]. My research team found that phytoncides released from trees significantly increased human NK activity and the intracellular levels of perforin, GrA, and GRN in human NK cells both in vitro [59] and in vivo [27]. Phytoncide exposure significantly decreased the concentrations of adrenaline and noradrenaline in urine, indicate that phytoncide exposure and decreased stress hormone levels may partially contribute to increased NK activity [27]. ...
Humans have enjoyed forest environments for ages because of the quiet atmosphere, beautiful scenery, mild climate, pleasant aromas, and fresh, clean air. In Japan, since 2004, serial studies have been conducted to investigate the effects of forest environments (Forest bathing/Shinrin-yoku) on human health. My research team has established a new medical science called Forest Medicine. The Forest Medicine is a new interdisciplinary science, belonging to the categories of alternative medicine, environmental medicine and preventive medicine, which studies the effects of forest environments (Forest bathing/Shinrin-yoku) on human health. It has been reported that Forest bathing/Shinrin-yoku has the following beneficial effects on human health:
1 Shinrin-yoku increases human natural killer (NK) activity, the number of NK cells, and the intracellular levels of anti-cancer proteins, suggesting a preventive effect on cancers.
2 Shinrin-yoku reduces blood pressure and heart rate showing preventive effect on hypertension and heart diseases.
3 Shinrin-yoku reduces stress hormones, such as urinary adrenaline and noradrenaline and salivary/serum cortisol contributing to stress management.
4 Shinrin-yoku increases the activity of parasympathetic nerves and reduces the activity of sympathetic nerves to stabilize the balance of autonomic nervous system.
5 Shinrin-yoku improve sleep.
6 Shinrin-yoku increases the levels of serum adiponectin and dehydroepiandrosterone sulfate.
7 In the Profile of Mood States (POMS) test, Shinrin-yoku reduces the scores for anxiety, depression, anger, fatigue, and confusion, and increases the score for vigor, showing preventive effects on depression.
8 Shinrin-yoku may apply to rehabilitation medicine
9 Shinrin-yoku in city parks also has benefits on human health.
10 Shinrin-yoku may have preventive effect on COVID-19 by boosting immune function and by reducing mental stress.
Taken together, these findings suggest that Shinrin-yoku may have potential preventive effects on non-communicable diseases.
... Previous studies reported that forest bathing enhanced NK cell activity, the number of NK and NKT cells, and intracellular anti-cancer proteins in lymphocytes [35][36][37]. Li et al. [35] reported that the increased NK activity was the leading cause of aromatic volatile substances derived from trees, called phytoncides, such as α-pinene and limonene. If phytoncide is inhaled while bathing in the forest, it is well known that it reduces cortisol, a stress hormone. ...
... Previous studies reported that forest bathing enhanced NK cell activity, the number of NK and NKT cells, and intracellular anti-cancer proteins in lymphocytes [35][36][37]. Li et al. [35] reported that the increased NK activity was the leading cause of aromatic volatile substances derived from trees, called phytoncides, such as α-pinene and limonene. If phytoncide is inhaled while bathing in the forest, it is well known that it reduces cortisol, a stress hormone. ...
Background: Forest bathing and aerobic exercise are known to be factors that increase natural killer (NK) cell, but it is considered to provide a greater effect when the two factors are combined. To date, it has not been studied whether aerobic exercise combined with forest bathing can further increase innate immunocytes, including NK cell. Therefore, this study investigated the effect of aerobic exercise + forest bathing on NK cell and whether stress hormones (epinephrine and cortisol) are involved in this physiological process. In addition, this study tried to confirm whether the mixed effect of the two had a more positive effect on cardiorespiratory endurance as well as body composition in the elderly men. Methods: Thirty-two participants were randomly assigned to one of four groups: control group (CON, n = 8) which was not provided with any intervention, exercise group (EXE, n = 8) which performed treadmill exercises without phytoncide, phytoncide group (PHYT, n = 8) which was provided with phytoncide intervention, and exercise + phytoncide group (EXE + PHYT, n = 8) which performed treadmill exercises and was provided with phytoncide. Treadmill exercises and phytoncide exposures were performed for 45~60 min a day, 3 days a week for 12 weeks. Results: Compared with CON, (1) the leucocytes and lympocytes of EXE, PHYT, and EXE + PHYT showed positive changes. Specifically, total NK cells, NKT cells, and NKG2D + NK of the EXE + PHYT increased after 12 weeks of intervention. (2) The cortisol concentrations of EXE, PHYT, and EXE + PHYT showed decreasing changes, whereas the epinephrine concentration were significantly increased. (3) Although there were no changes in the muscle mass of EXE, PHYT, and EXE + PHYT, cardiorespiratory endurance was significantly increased in those groups. In addition, the body weight, fat mass, and fat percentage significantly decreased only in the EXE + PHYT. Conclusions: This study confirmed that forest bathing and aerobic exercise positively affected immunocyte function in elderly men. It also found that the improved results from forest bathing + treadmill walking were caused by an increase in cardiorespiratory endurance by increased epinephrine concentrations. In addition, this increased cardiorespiratory endurance can be interpreted as significantly reducing the body weight and fat in the group that participated in the exercise combined with phytoncide exposure.
... Elderly patients with chronic pulmonary diseases gained more health benefit from breathing exercises when performed in forests (Bing et a., 2016). This can be attributed to breathing in phytoncides, which are antimicrobial volatile organic compounds derived from trees, which improves immunity (Ohtsuka et al., 1998;Li et al., 2006). It has also been reported that psychiatric treatment for children was more effective when paired with nature therapy at a beach (Berger and Tiry, 2012). ...
... In ancient Rome, it was common for people to periodically take refuge in forested areas to deal with urban congestion (Glacken, 1967). Some researchers believe the healing powers of nature is primarily due to phytoncides, a volatile substance emitted by plants Li et al. (2006). Song et al. (2016) discovered that indoor exposure to forest derived phytoncides could increase NK cell activity and improve overall immunity function. ...
The Coronavirus disease-2019 (COVID-19) pandemic has affected over 200 countries, forcing governments to impose lockdowns to contain the spread of the disease. Although effective in reducing infection rates, the lockdowns have also resulted in a severe negative impact on mental health throughout the world; Setting the foundation for mental illnesses to become the next “silent” pandemic. This study attempts to determine a self-care method of ensuring mental health during the COVID-19 pandemic, especially for those living under lockdown. We evaluated the potential of physical exercise (in a nature setting) and nature therapy in improving mental wellbeing, among young adults with either stress, anxiety or depression symptoms. The study involved thirty subjects, who were equally divided into a nature-exercise group and a nature therapy group. The participants were briefed on the activities that they were to perform on a daily basis, and both groups performed their assigned activities concurrently for one week (27th April 2020 to 3rd May 2020) at urban greeneries accessible to them (rooftop parks, neighbourhood parks, home gardens). We used the depression, anxiety and stress scale – 21 items (DASS-21) to evaluate the mental health status of participants, once before beginning the study (baseline readings) and once at the end of the study (after a week of nature-exercise/nature therapy). There was a statistically significant reduction in stress, anxiety and depression symptoms for both the nature-exercise and nature therapy groups. However, when evaluating the effectiveness of exercise and nature therapy in treating stress, anxiety and depression symptoms on a case-by-case basis, it was discovered that nature therapy was more effective in treating mental health issues. Hence, nature therapy has the potential to be a form of preventive medicine, namely in preserving mental health during the COVID-19 crisis.
... Forest bathing stabilizes autonomic nervous activity and significantly decreases the concentrations of stress hormones such as adrenaline and noradrenaline [75,77,78]. The frequency and count of NK cells, and the expression levels of granulysin, perforin, and granzymes A/B on NK cells increased on the forest bathing days, resulting in an increase in NK cell activity [75][76][77][78][79]110]. The increased NK cell activity lasted for more than 30 days after the trip [75,77,79]. ...
... The increased NK cell activity lasted for more than 30 days after the trip [75,77,79]. The mechanisms underlying the increased NK cell activity during forest bathing may be partially related to an attenuated stress hormone response and also to breathing in of volatile organic compounds, called phytoncides produced by trees, such as α-pinene and limonene [75][76][77]110]. In vitro research data indicate that phytoncides increase NK cell activity in a dose-dependent manner and prevent dichlovos-induced inhibition of NK cell activity [79]. ...
Natural killer (NK) cells are cytotoxic immune cells with an innate capacity for eliminating cancer cells and virus- infected cells. NK cells are critical effector cells in the immunosurveillance of cancer and viral infections. Patients with low NK cell activity or NK cell deficiencies are predisposed to increased risks of cancer and severe viral infections. However, functional alterations of human NK cells are associated with lifestyles and aging. Personal lifestyles, such as cigarette smoking, alcohol consumption, stress, obesity, and aging are correlated with NK cell dysfunction, whereas adequate sleep, moderate exercise, forest bathing, and listening to music are associated with functional healthy NK cells. Therefore, adherence to a healthy lifestyle is essential and will be favorable for immunosurveillance of cancer and viral infections with healthy NK cells.
... On the other, strong tourism governance might favor the development of such FCIs. The analysis, however, did not significantly fill the information gap about the preferred and more suitable hosting ecosystems for FCIs [59]. About 66% of the FCIs were located in the north of the country (Figure 2b), in particular in the northeastern regions (e.g., Trentino-Alto Adige/Südtirol, Veneto, Friuli-Venezia Giulia, and Emilia-Romagna). ...
... On the other, strong tourism governance might favor the development of such FCIs. The analysis, however, did not significantly fill the information gap about the preferred and more suitable hosting ecosystems for FCIs [59]. ...
In the effort to advance the knowledge of and disentangle the diversity of emerging forest-based initiatives for wellbeing, we propose (1) an umbrella definition (i.e., forest care initiatives (FCIs)), (2) a custom-made repository to collect and systematize information on FCIs in Italy, and (3) discuss a categorization scheme to cluster initiatives into three main categories according to target users, substitutability of the forest ecosystem, and the specificity of the health contributions to which they are aimed. We analyzed 232 initiatives, showing a lively panorama of Italian FCIs, mainly provided by private entities and civil society. FCI developments appear to be occasions for, but are not restricted to, rural and marginal areas delivering inclusive wellbeing services to a wide target user group and business opportunities. However, due to the novelty of this area of investigation, further research is needed to account for benefits and opportunities and to increase knowledge on enabling forest environments.
... Terpenoids are the most common secondary metabolites in plants, including monoterpenes, sesquiterpenes, diterpenoids or triterpenoid derivatives (Hegazy et al., 2020), and many terpenoids have medicinal value, such as α-pinene, limonene, etc. Ateba et al. (2018) reported that costunolide and triptolide can inhibit the proliferation, migration, anti-apoptosis, tumor angiogenesis or metastasis of different breast cancer cells or tumors. Li et al. (2006) reported that granzyme, granulin and perforin levels of cell were significantly increased by using α-pinene and other substances contained in the volatiles to cultivate Nk-92mi cells. 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR), l-deoxy-D-xylulose-5-phosphatesynthase (DXS), 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) and terpene sythases (TPS) are the key enzymes in the synthetic pathway of mevalonate (MVA) and 2-methyl-d-erythritol-4-phosphate (MEP). ...
... Hormones can play an important role in the regulation of plant metabolism, and there are many hormone response elements in the promoter of TPS gene. ZmTPS6 gene of maize can be significantly up regulated in GA, MeJA and ABA treatments (Li et al., 2006). And we have found that MoTPS3 gene promoter also has many hormone response elements (Table 1), such as auxin, GA, MeJA response elements. ...
... Moreover, in light of the COVID-19 pandemic, they play an important role in managing the physical and mental well-being of humans who can access 239 forests for nature-based tourism and recreation. This includes physical health benefits such as oxygenated air and pollutant amelioration (Karjalainen et al. 2010, Nowak, 2002 and the support of immune system functioning through phytoncide release (Karjalainen et al. 2010, Li et al. 2006) as well as mental health benefits such as blood-adrenaline reduction (Li 2010) and the reduction of prefrontal brain activity signifying stress-relief ). The body of research provides evidence supporting the notion that getting people back into larger contigous natural areas such as forests through managed nature-based tourism and recreation, is important for reducing human stress levels. ...
... For forest therapy and forest bathing however, the benefits subject to most research have been those associated with health ( Figure 1). Positive physiological effects of forest therapy have been reported on the cardiovascular system (such as reducing heart rate and blood pressure) (Ohtsuka et al. 1998, Hartig et al. 2003, Tsunetsegu et al. 2007, Park et al. 2008, Lee et al. 2009, Kjellgren and Buhrkall 2010, Li et al.2011, Lee et al. 2011, Mao et al. 2012, Tsunetsugu et al. 2013, Song et al. 2015, Hansen et al. 2017, Ideno et al. 2017, Yu et al. 2017, immune and endocrine systems (such as increase in natural killer cells/anti-cancer protein production and reducing blood-sugar levels) (Ohtsuka et al. 1998, Li et al. 2006, Li et al. 2007, Li et al. 2008b, Li et al. 2008c, Li 2010, Li et al. 2011, Lee et al. 2009, Nakau et al. 2013, gastrointestinal tract (such as stomach ulcer recovery and easing digestion) Kawada 2014, Kim et al. 2019), respiratory system (such as allergies and respiratory diseases) (Seo et al. 2015, Hansen et al. 2017, Edwards and Woods 2018 and nervous system (such as decreasing the level of cortisol and other stress hormones) (Yamaguchi et al. 2006, Lee et al. 2009, Lee et al. 2011, Lee et al. 2014, Tsunetsegu et al. 2007, Tsunetsegu et al. 2010, Park et al. 2008, Jung et al. 2015, Yu et al. 2017. Positive psychological effects can be seen on mental health and emotional well-being by reducing stress, depression, anger, fatigue, confusion, improving mood, concentration and memory, increasing sense of relaxation and helping in the treatment of eating disorders (Yamaguchi et al. 2006, Corazon et al. 2010, Martens et al. 2011, Mao et al. 2012, Song et al. 2013, Craig et al. 2016, Hansen et al. 2017, Yu et al. 2017, Mathias et al. 2018, Clifford 2018, Li 2019. ...
Forest therapy and forest bathing constitute more than just a walk in the
woods. Unlike hiking, there is no particular destination and no physical
exertion required, it is an exercise for the mind, not the body (Li, 2019). These
emerging industries deserve more detailed investigation into their potential
benefits in holistically managing the fallout of COVID-19 and other global
health concerns. Research is needed into the sustainable planning of suitably designed
trail routes for forest therapy and forest bathing, especially in
countries currently downgrading the importance of tourism and recreation
planning such as Turkey.
... Kato, denominada "shinrin-yoku"(LI, 2010(LI, , 2018, que significa "absorver a atmosfera da floresta". De acordo comLi et al. (2008), phytoncides são exalados durante o processo de evapotranspiração, também típico nas florestas ombrófilas densas de mata atlântica. Acredita-se que a inalação e até a simples precipitação desses elementos possam de alguma forma atuar beneficamente na fisiologia humana.Nesse contexto, com auxílio do guia local, foi possível selecionar indivíduos arbóreos ao longo da trilha do Jequitibá-Cristais, relacionando-os com as propriedades fitoterápicas.Ao longo das trilhas do Jequitibá, foram identificados taxonomicamente inúmeros indivíduos arbóreos com tradição de uso popular de suas essências, sendo comparados com resultados divulgados por inúmeras pesquisas acadêmicas.Ao longo do bordo da trilha foram escolhidas 10 espécies vegetais arbóreas encontradas no complexo de trilhas do Jequitibá-Cristais com o intuito de iniciar um estudo preliminar de suas propriedades fitoterápicas e dos phytoncides produzidos por esses indivíduos arbóreos. ...
... Exposure to the forest environment is associated with greater resistance to future stressors and faster regeneration after a stressful experience, suggesting that forests are important in the prevention of mental and neurodegenerative diseases (Annerstedt et al. 2013). Being in the forest may also strengthen the immune system (Li et al. 2006). People's reliance on access to nature as a source of health during the COVID-19 pandemic was a worldwide phenomenon (Naomi 2020;Weinbrenner et al. 2021). ...
Given the enormous global impact of the COVID-19 pandemic, outbreaks of highly pathogenic avian influenza in Canada, and manifold other zoonotic pathogen activity, there is a pressing need for a deeper understanding of the human-animal-environment interface and the intersecting biological, ecological, and societal factors contributing to the emergence, spread, and impact of zoonotic diseases. We aim to apply a One Health approach to pressing issues related to emerging zoonoses, and propose a functional framework of interconnected but distinct groups of recommendations around strategy and governance, technical leadership (operations), equity, education and research for a One Health approach and Action Plan for Canada. Change is desperately needed, beginning by reorienting our approach to health and recalibrating our perspectives to restore balance with the natural world in a rapid and sustainable fashion. In Canada, a major paradigm shift in how we think about health is required. All of society must recognize the intrinsic value of all living species and the importance of the health of humans, other animals, and ecosystems to health for all.
... A propensity score matching analysis was then performed, considering an aboveaverage exposure to inhalable air MTs as the treatment: the estimated effect was -1.28 STAI-S points (95% C.I. -2.51 to -0.06, p = 0.04), indicating that the average effect of exposure to high MT air concentrations during forest therapy sessions is to decrease anxiety. determinants of the interaction between forest ecosystems and human health [17][18][19][20], especially those related to long-lasting effects on the immune system after forest exposure [18,[21][22][23][24][25]. ...
Immersive experiences in green areas and particularly in forests have long been known to produce beneficial effects for human health. However, the exact determinants and mechanisms leading to healthy outcomes remain to be elucidated. The purpose of this study was to investigate whether inhaling plant-emitted biogenic volatile compounds, namely monoterpenes (MTs), can produce specific effects on anxiety. Data from 505 subjects participating in 39 structured forest therapy sessions in different Italian sites, were collected. Monoterpenes air concentration was measured at each site. STAI State questionnaires were administered before and after the sessions as a measure of anxiety. A propensity score matching analysis was then performed, considering an above-average exposure to inhalable air MTs as the treatment: the estimated effect was -1.28 STAI-S points (95% C.I. -2.51 to -0.06, p = 0.04), indicating that the average effect of exposure to high MT air concentrations during forest therapy sessions is to decrease anxiety.
... El mecanisme de funcionament és a través de la inhalació de compostos orgànics volàtils (phytoncides com el limonè i l'alfa-pinè) que alliberen els arbres de boscos vells i que tenen un efecte estimulant sobre el sistema immunitari, a més de potenciar l'activitat antimicrobiana, reduir el nivell d'estrès del pacient (mesurat en els nivells d'adrenalina en orina i en la tensió arterial) i augmentar els nivells d'adiponectina, proteïna que prevé la diabetes mellitus, malalties cardiovasculars i l'obesitat. Els diferents estudis publicats (Li et al., 2006(Li et al., , 2007 mostren el detall dels mecanismes que entren en funcionament, essent el resultat més destacable l'estimulació de les cèl·lules citocides NK que indueixen l'apoptosi de les cèl·lules tumorals. ...
Evidence of the effect of contact with natural areas on people's health.
Els professionals de la conservació del patrimoni natural, per sort o per desgràcia, ens trobem contínuament amb la ne-cessitat de justificar el perquè de la nostra feina. Al llarg de la història del nostre sector hem anat explorant diferents apro-ximacions a la qüestió: des d'intentar explicar el valor patri-monial d'espècies i hàbitats per se fins a l'intent d'avaluació econòmica dels productes i serveis que els sistemes naturals ens proveeixen. I és que com més urbana es va tornant la nos-tra societat, més cal recordar allò que intuïtivament ja saben els que es dediquen a la producció primària no intensiva: l'espècie humana forma part del sistema natural i com a tal, s'hi troba bé. Des de la Fundació Catalunya-La Pedrera, es van orga-nitzar unes jornades els proppassats 22 i 23 de setembre per donar a conèixer els resultats dels primers estudis científics que busquen evidències de la hipòtesi que el contacte directe amb els sistemes naturals afavoreix la salut de les persones (Fig. 1). Aquest escrit busca ser un recull dels punts que, a criteri del tot subjectiu dels autors, poden ser més rellevants pel nostre sector. Les presentacions realitzades, els ponents que hi van participar i les gravacions de les ponències estan disponibles al web: www.fundaciocatalunya-lapedrera.com/ ca/territori-i-mediambient/salut-i-natura Per començar, voldríem destacar de la primera ponència sobre el projecte europeu PHENOTYPE a càrrec de Mark Nieuwenhuijsen del Centre de Recerca en Epidemiologia Ambiental de Barcelona (CREAL), el recull d'articles cien-tífics que evidencien la percepció intuïtiva que els espais naturals ajuden a reduir l'impacte de malalties a la població o a afavorir la recuperació dels pacients. N'hi ha molts. Desta-quem com a primera cita un article d'Ulrich (1984) publicat a Science on es recollia que els pacients d'un hospital que es recuperaven de cirurgia de vesícula en habitacions amb vis-tes a zones verdes es recuperaven abans i necessitaven menys calmants que els pacients allotjats en habitacions sense vis-tes a zones verdes; a més, tenien millor percepció del tracte rebut pel personal d'infermeria. També que la recuperació davant d'una situació estressant és més ràpida si la persona s'exposa a zones verdes (Ulrich et al., 1991); que les per-sones que caminen habitualment en zones verdes viuen més anys segons un estudi realitzat al Japó (Takano et al., 2002)
... These secondary plant metabolites are used by plants to protect against herbivores and pathogenic micro-organisms, but they have also been shown to exhibit strong anti-inflammatory and antioxidant properties, and can stimulate autophagy [199]. Indeed, an early experiment by Li et al. [200] demonstrated that phytoncides are independently able to influence immune cell function in vitro, therefore suggesting that one benefit of forest bathing may be exposure to beneficial volatile organic compounds often found in relatively higher concentrations in forests [186]. ...
This review shows that relatively simple changes to diet and lifestyle can significantly, and rapidly, reduce the risks associated with coronavirus disease 2019 (COVID-19) in terms of infection risk, severity of disease, and even disease-related mortality. A wide range of interventions including regular exercise, adequate sleep, plant-based diets, maintenance of healthy weight, dietary supplementation, and time in nature have each been shown to have beneficial effects for supporting more positive health outcomes with COVID-19, in addition to promoting better overall health. This paper brings together literature from these areas and presents the argument that non-pharmaceutical approaches should not be overlooked in our response to COVID-19. It is noted that, in several cases, interventions discussed result in risk reductions equivalent to, or even greater than, those associated with currently available vaccines. Where the balance of evidence suggests benefits, and the risk is minimal to none, it is suggested that communicating the power of individual actions to the public becomes morally imperative. Further, many lives could be saved, and many harms from the vaccine mandates avoided, if we were willing to embrace this lifestyle-centred approach in our efforts to deal with COVID-19.
... After the practice, patients reported lower concentrations of cortisol, lower pulse rate, lower blood pressure as well as greater parasympathetic nerve activity, and lower sympathetic nerve activity than in city environments [64]. Various studies suggested that even just the essential oils from plants can stimulate the immunological function of our organisms [65,66], which is fundamental for fetal and maternal wellbeing. Women should be therefore encouraged to "forest bathe" as frequently as they can. ...
Objective: The environmental crisis we are experiencing is becoming a more popular topic of expert discussion and analysis. Human activity and expansion on the planet are exacerbating climate change and global warming, this, together with the increase in plastic production, and general pollution, posing a threat to our resources, supplies, and survival. This research aims to review what is known about the association between pollution and pregnancy and sensitize experts to women’s education towards healthier behaviors. Mechanism: We chose to focus on the effects of the environment on fetal development and maternal health, considering various studies that highlight the potential consequences of exposure to certain environmental stressors. The paper briefly illustrates the probable mechanisms that, starting from cellular and intracellular damage, determined above all by plastics, lead to chronic activation of the immune system in response to danger and, therefore, to epigenetic modifications at the base of diseases in adulthood. Findings in Brief: We describe the effects of the main pollutants on pregnancy, with particular attention to the role of plastic. Finally, we briefly outline some individual possible solutions to this complex problem. Conclusions: In the era of environmental crisis, becoming aware of the mechanisms behind biological damage resulting from exposure to certain pollutants and plastics, especially in a period as sensitive as pregnancy, should be the driving force behind a change of direction. As physicians, this means educating our patients and recommending individual solutions to reduce the impact of contaminants to provide the best possible environment for women’s and children’s health, especially during the delicate period of pregnancy; but the ultimate solution is to drastically reduce global plastic production and pollution, and to recycle the plastic that is needed anyway.
... These studies have clearly shown that forest bathing can benefit human immune function. Studies have also speculated that phytoncides released by trees may be partly responsible for the increased NK activity [12,13,[30][31][32][33][34]. , also examined the relationship between forest cover rate and cancer mortality and revealed significant negative correlations between forest cover rates of all prefectures in Japan and the mortality due to lung, breast, and uterine cancer in women and prostate, kidney, and colon cancer in men [35]. ...
Forests have provided support for human health and survival since ancient times. With improved public awareness of health issues and the importance of forest ecological functions, forest therapy has gradually gained momentum. Forest therapies have been applied around the world as preventive and alternative therapies to promote human health. As a safe, side-effect-free, low-cost, preventive, and alternative therapy, forest therapy has been scientifically proven to promote physical and mental health in humans. However, the forest therapy service system is still underdeveloped, and forest therapy has not become a mainstream part of clinical medical treatment methods in most countries worldwide. Therefore, in order to better present the development path and current situation of forest therapy in different countries and provide guidance for how other countries can develop similar interventions and clinical sites to base these activities, this study uses Germany, Japan, and China as examples to systematically tease out how forest therapy has developed and the status of forest therapy services in different countries, as well as the health benefits of forest therapy. Furthermore, the key components and traditional cultural and socioeconomic backgrounds related to forest therapy are discussed. Finally, based on published empirical research, we believe that forest therapy can be a solution to public health problems thanks to its multiple, medically proven health benefits. Forest therapy facilitates the return of people to the forest and nature to achieve health and well-being effects. However, there is a need for more research on the mechanisms (such as the immune system, endocrine system, nervous system, etc.) underlying forest therapy’s effectiveness, which should include strengthened collaborations between disciplines. In addition, the role of forest therapy services in promoting human health needs to be emphasized.
... These results suggest that chlorpyrifos-methyl generally affects mechanisms associated with detoxification, cytolytic capacity and redox signaling in cod leukocytes. It has been reported that organophosphorus pesticides like chlorpyrifos-methyl diminish natural killer cells and cytotoxic activities in aquatic and human models through different and indirect mechanisms [53][54][55]. Also reported, organophosphorus pesticides induced apoptosis in cultured human lymphocytes of peripheral blood [56] and chlorpyrifos-methyl induced apoptosis and increased apoptotic gene casp3 in the human monocyte cellular line U937 [57]. ...
Inclusion of new environmental toxicants increase with the amount of plant ingredients substituting marine proteins and oils in feed for farmed Atlantic salmon (Salma salar). Agricultural pesticides like chlorpyrifos-methyl, present in commercial salmon feeds, may affect salmon immune and detoxification responses. Atlantic cod (Gadus morhua), surrounding the net pens, grazing on feces and uneaten pellets may be affected accordingly. The aim of this study was to analyze transcription responses in Atlantic cod head kidney tissue and isolated leukocytes following dietary chlorpyrifos-methyl inclusions and possible interactions with proinflammatory signals. Head kidney tissues and leukocytes were isolated from cod fed diets contaminated with chlorpyrifos-methyl (0.5 mg/kg, 2.4 mg/kg, 23.2 mg/kg) for 30 days. The isolated leukocytes were further challenged with bacteria (lipopolysaccharide (LPS), virus (polyinosinic acid:polycytidylic acid (PIC) mimic and l-arginine, an immuno-modulating amino acid, in vitro.
The LPS-induced transcription of the interleukin genes il-1β, il-6, il-8 increased in leukocytes isolated from cod fed chlorpyrifos-methyl 23.2 mg/kg, compared to cod fed the control diet, indicating increased inflammation. Transcriptional levels of carnitine palmitoyl transferase (cpt1a), aryl hydrogen receptor (ahr) and catalase (cat) were all reduced by dietary inclusions of chlorpyrifos-methyl in the leukocytes. The findings suggests that dietary chlorpyrifos-methyl exposure impair inflammation, detoxification and redox signaling in cod leukocytes.
... Finally, it has recently been discovered that the reduction in stress and improvements to the immune system produced by forest visits can be replicated when evergreen oils are removed from trees, aerosolized, and infused in interior spaces [77]. The essential oils emitted by evergreen trees are associated with improvements to the immune system and the production of natural killer cells [78,79]. These effects could be long-term but vary based on gender, with immune functions increased for up to 30 days in men and only seven in women [80]. ...
In recent years, work-related stress has grown exponentially and the negative impact that this condition has on people’s health is considerable. The effects of work-related stress can be distinguished in those that affect workers (e.g., depression and anxiety) and those that affect the company (e.g., absenteeism and productivity). It is possible to distinguish two types of prevention interventions. Individual interventions aim at promoting coping and individual resilience strategies with the aim of modifying cognitive assessments of the potential stressor, thus reducing its negative impact on health. Mindfulness techniques have been found to be effective stress management tools that are also useful in dealing with stressful events in the workplace. Organizational interventions modify the risk factors connected to the context and content of the work. It was found that a restorative workplace (i.e., with natural elements) reduces stress and fatigue, improving work performance. Furthermore, practicing mindfulness in nature helps to improve the feeling of wellbeing and to relieve stress. In this paper, we review the role of mindfulness-based practices and of contact with nature in coping with stressful situations at work, and we propose a model of coping with work-related stress by using mindfulness in nature-based practices.
... Essential oils from different coniferous species and specific terpenes: α-pinene, 1,8-cineole, and d-limonene were used to examine their impact on NK cells. It was concluded that these compounds significantly increased and even restored the lost activity of NK cells [46]. Further on, these findings were confirmed within in vivo experiments in the forest [47] and afterward in unnatural environments where participants were exposed to inhaling the essential oils of previously used conifer species [48]. ...
Numerous medical studies have shown the positive effects of forests on different aspects of human health. This study deals with the content of major terpenes in dominant coniferous species in Tara National Park, Serbia, in order to explore the potential for the development of a novel health tourism programme based on forest therapy. Main terpenes were analysed using a headspace-sampling technique coupled with gas-chromatography-mass spectrometry (Head-space-GC/MS). Needles of fir and spruce growing in the vicinity of hiking trails were investigated for possibilities to perform such therapy. Major detected terpenes were α-cadinol and spathulenol previously described as antiviral, antitumor, antimicrobial and immunomodulatory agents. The results of the study were favourable and worked well with the existing walking infrastructure in the observed area of the Tara Mountain, as they act as invaluable resources for designing the structured forest bathing walks. The study not only adds to the knowledge in the environmental and public health realm but also to tourism and sustainability studies.
... They are volatile chemicals emitted by plants to defend against viruses, bacteria, saccharomyces, molds, and protozoans [69] or to prevent decay and herbivore attacks. Phytoncides also exhibit other beneficial effects, such as anti-microbial, antibacterial [70], anti-fungal, anti-inflammatory, anti-stress, analgesic, and anti-spoilage activities, and they can be used as food preservatives [36,[71][72][73][74][75][76][77][78][79][80][81][82]. They also exhibit anti-mycoplasmal activity [83], anti-larvicidal activity against malaria [84,85] and dengue [86], anti-septic activity, and anthelminthic activity; in addition, they facilitate wound healing [87], can act as cholesterol inhibitors [88], can enhance sleep [89][90][91], and even enhance bacterial susceptibility to antibiotics [92,93]. ...
Chemical compounds from plants have been used as a medicinal source for various diseases. Aromachology is a unique field that studies the olfactory effects after inhaling aromatic compounds. Aromatherapy is a complementary treatment methodology involving the use of essential oils containing phytoncides and other volatile organic compounds for various physical and mental illnesses. Phytoncides possess an inherent medicinal property. Their health benefits range from treating stress, immunosuppression, blood pressure, respiratory diseases, anxiety, and pain to anti-microbial, anti-larvicidal, antiseptic , anti-cancer effects, etc. Recent advancements in aromatherapy include forest bathing or forest therapy. The inhalation of phytoncide-rich forest air has been proven to reduce stress-induced immunosuppression, normalize immune function and neuroendocrine hormone levels, and, thus, restore physiological and psychological health. The intricate mechanisms related to how aroma converts into olfactory signals and how the olfactory signals relieve physical and mental illness still pose enormous questions and are the subject of ongoing research. Aroma-therapy using the aroma of essential oils/phytoncides could be more innovative and attractive to patients. Moreover, with fewer side effects, this field might be recognized as a new field of complementary medicine in alleviating some forms of physical and mental distress. Essential oils are important assets in aromatherapy, cosmetics, and food preservatives. The use of essential oils as an aromatherapeutic agent is widespread. Detailed reports on the effects of EOs in aromatherapy and their pharmacological effects are required to uncover its complete biological mechanism. This review is about the evolution of research related to phytoncides containing EOs in treating various ailments and provides comprehensive details from complementary medicine.
... Forest air contains less dust and gas pollutants, is richer in oxygen, and saturated with essential oils produced by plants (Nowak et al., 2014). The oils also include substances with antibacterial properties comparable to those of antibiotics -phytoncides (Li et al., 2006(Li et al., , 2009. Moreover, daily and annual changes in atmospheric conditions take a milder course, and noise pollution is replaced by the sounds of nature. ...
The largest areas in 23 Polish National Parks are occupied by forests. They include the Świętokrzyski, Roztoczański, Białowieski, and Kampinoski National Parks, where forests cover from 75 to 95% of their area. The recreational layer bioclimate occurring in the forest areas of these parks were investigated. The forest microclimate considerably differs from that which occurs in non−forest areas. Moreover, different forest communities have a different effect on the human organism. The primary objective of the study is a comparative analysis the recreational bioclimate of forest communities along tourist trails in the Białowieski, Świętokrzyski, Kampinoski, and Roztoczański National Parks, with consideration of their health benefits. The forest communities of the analysed parks are dominated by forests with a favourable bioclimate: 62−87%, with the exception of BNP, where they occupy only 11% of the area. Communities with an unfavourable bioclimate cover 22% and 15% of BNP and KNP; in the remaining two parks they cover <5% of the forests. In three of the four national parks analysed, a large majority of tourist trails run through communities with favourable bioclimatic conditions (90% in SNP, 77% in the RNP, and 73% in the KNP), with the exception of BNP (19%). Unfavourable bioclimates are only found on BNP (12%) and KNP (3%) trails. Statistical analysis shows a similarity between the analysed parks in terms of the recreational bioclimate occurring on tourist trails, with the exception of the Białowieski National Park, which is statistically different from the others.
... During their life activity, plants produce volatile organic compounds, phytoncides, protecting themselves from diseases. Phytoncides are bactericidal, protistocidal, and fungicidal substances produced by higher and lower plant organisms for protection and healing purposes (Tokin, 1951;Li, 2006). Nature-based tourism accounts for 7% of all international travel worldwide (Li et al., 2010;Herman et al., 2019). ...
The article presents the prospects for the development of natural and recreational activities in the field of medical and health tourism within the ribbon pine forest, located in the southern outskirts of the West Siberian dry steppe lowland. The purpose of the study is to assess the biological and geographical potential of the forest landscape for the development of recreational areas. This is especially true for the Northern region of Kazakhstan, since industry is developed on the territory, it is characterized by technogenesis. Research methods include field reconnaissance, cartographic modeling using GIS technologies, and laboratory experiments to determine the phytoncide activity of the biological material of trees – Scots pine – collected at different intervals of the day. The results of the study are statistical data on laboratory research. For convenience, they are presented in the form of cartographic material, built based on spatial data of the territory. The paper considers and addresses the ecosystem’s natural potential and the recreational infrastructure of the studied object.
... The health benefits of nature have been identified as one of many essential and life-supporting goods that nature provide to humanity, namely ecosystem services [17,18]. Evidence suggests that nature exposure benefits mental health [19][20][21][22][23][24][25], physical health [26][27][28][29] and immune function [30][31][32]. ...
Exposure to nature has been suggested to promote immigrants’ health and facilitate adaptation. This review summarizes previous research focusing on the relationship between nature and immigrants’ integration, wellbeing and physical activity. A search strategy was developed and adapted to seven databases. After removing duplicates, 4861 records were screened, 81 met inclusion criteria. Community gardens and urban parks were the most studied environments. In these settings, embodied experiences (the interactive processes of sensing and cognition) can foster new memories that facilitate adaptation and attachment to new natural environments. Social interaction and reconnecting with pre-migration experiences through specific use patterns can promote cultural continuation, sense of belonging and wellbeing. Other health benefits such as physical activity, disease management and improved nutrition were less frequently studied. Barriers to participation and recommendations for research and practice were also identified. Use of stronger study designs and greater inclusion of immigrant groups in research, design and evaluation of nature-based initiatives is needed.
... Breathing in the forest's 'volatile' substances can help to reduce stress or enhance rehabilitation and concentration (Hansen et al., 2017;Park, Tsunetsugu, Kasetani, Kagawa, & Miyazaki, 2010). The phytoncides, aromatic molecules released by trees, prompt our bodies to boost the natural killer (NK) cells that attack infections and guard against tumours (Li, 2010;Li et al., 2006). It has been argued that forest bathing can prevent illnesses caused by stress, burn-out and depression, as well as help to establish personal and community identity, social activity, and social participation (Morton, Ferguson, & Baty, 2015). ...
In the troubled times in which we currently live, the tourism industry has called into question a need for more responsible social practices and more mindful utilisation of natural environments. The Japanese practice of shinrin-yoku, or forest bathing, has not only become a new wellness trend, but also a great potential for deeply immersive tourist experiences. While there is a wealth of studies examining the positive effects of forest bathing focussing principally on its medical benefits, this qualitative study extends these debates through documenting lived experiences of forest bathers. In so doing forest bathing suggests its latent potential to offer a profoundly mindful experience, and aims to situate this practice more prominently within the tourism discourse.
... A number of studies [1,7,8,38,48,49] reported that volatile substances (phytoncides) extracted from trees have a positive effect on immune function, supporting the idea that a forest's environmental factors play an instrumental role in improving immune function. An in vitro study indicated that certain volatile tree chemicals, called phytoncides, increase the activation of NK cells and intracellular anti-cancer molecules [50]. This assertion is supported by several studies in animals [51,52] and humans [53], suggesting that fragrances from trees can reverse stress-induced immunosuppression, and normalize immune function and neuroendocrine hormone levels. ...
We conducted a systematic review of the effects of a forest therapy program on adults’ immune function. We used PICO-SD (participants, interventions, comparisons, outcomes, study design) to identify key items. The participants were adults over the age of 18 and the intervention was forest therapy. Our comparisons included studies that comparatively analyzed urban groups or groups that did not participate in forest therapy intervention. Cases without control groups were also included. Immunological outcome measures were included in measuring intervention outcomes. All experimental studies, such as randomized controlled trials (RCTs), non-equivalent control group designs (non-RCTs), and one-group pretest-posttest design were included in the study design. A total of 13 studies were included for comparison. Forest therapy programs were divided into lodging-type and session-type programs. The representative measures for evaluating the effects of immune function were the number of NK cells, the cytotoxic activity of NK cells, and cytotoxic effector molecules. Most studies reported improvement in these measures when comparing values after intervention with values before the forest therapy intervention. Therefore, forest therapy has been found to be effective in improving immune function. More RCT studies on the effects of forest therapy on immune function are necessary.
... Several studies have demonstrated a beneficial effect of forest therapy on human's weakened immune function (Li, 2010;Li et al., 2007;Lyu et al., 2019). These effects might be due to plant-derived phytoncides, which are antimicrobial volatile organic compounds that have been shown to reduce blood pressure, alter autonomic activity, and boost immune function by increasing the concentrations and activity of natural killer (NK) cells, among other effects (Komori et al., 1995;Li et al., 2006). ...
This study examined the associations between green spaces and one–years' worth of SARS–CoV–2 infection rates across all 3,108 counties in the contiguous United States after controlling for multiple categories of confounding factors. We found green spaces at the county level have a significant negative association with infection rates. Among all types of green spaces, forest yields the most consistent and strongest negative association. Sensitivity analyses confirmed the negative association of forest across five urbanicity levels, and the strength of the association increases as disease incidence increases across five time periods. Although forest located in moderately urbanized counties yields the strongest association, the negative pattern of significant associations holds across all five urbanicity levels. A population–weighted analysis revealed that proximity to forest within a moderate walking distance (≤ 1.0–1.4 km) may provide the greatest protection against the risk of infection.
... In addition, Stanhope, et al. [14] proposed other potential reasons for pain relief in a short-term greenspace exposure. For instance, phytoncides may influence the human immune system, enhance natural killer cells' activity and treat some types of pain [51,52]. ...
Reducing the burden of pain via greenspace exposure is a rising research topic. However, insufficient evidence has been found in relation to the environmental effect itself. Residential greenspace, as a convenient but limited natural environment for urban dwellers, has benefits and services yet to be discovered. Therefore, the current study recruited 24 young adults to evaluate the effects of physical visit to, or image viewing of, residential greenspace on pain perception and related psychophysiological outcomes, via simulated pain. Pain threshold and tolerance were recorded via the level of pain stimuli, and pain intensity was evaluated using the Visual Analog Scale (VAS). The state scale of the State–Trait Anxiety Inventory (STAI-S) and two adjective pairs were employed to measure the state anxiety and subjective stress, respectively. Meanwhile, heart rate (HR), heart rate variability (HRV), and blood pressure (BP) were measured to investigate physiological responses. Besides, Scenic Beauty Estimation (SBE) was also employed to assess participants’ preference regarding the experimental environments. The results revealed that visiting the greenspace significantly increased the pain threshold and tolerance, while no significant effect was observed for image viewing. On the other hand, no significant difference was observed in pain-related psychophysiological indices between the experimental settings, but significantly negative associations were found between the scores of SBE and subjective stress and state anxiety. In conclusion, the current study brings experimental evidence of improving pain experience via residential greenspace exposure, while the related psychophysiological benefits require further investigation.
... Moreover, the type of the forest at the experimental sites also has a great influence on the forest air, the compounds, and the concentrations of phytoncides present in the air. Various phytoncides from coniferous trees significantly increased human NK activity and the expression of perforin, granulysin, and granzyme A in in vitro experiments [71] and raised the percentages and activity of NK cells as well as the expressions of perforin, granulysin, and granzyme A/B in in vivo human studies [72]. High concentrations of phytoncides were detected in the coniferous forests in the works of Li and colleagues [1], while our study took place in a deciduous forest; moreover, we did not collect and analyze forest air samples, which is a limitation of our experiment. ...
Various formats of forest bathing have been receiving increasing attention owing to their perspectives in health promotion and the treatment of chronic lifestyle diseases. The majority of field studies are still being conducted in the Far Eastern region, and they often make psychological assessments mainly in the green season. In our pretest–posttest field experiment, twelve healthy, working-age volunteers participated in a 2-h leisurely forest walking program, first in the green season (May) and then in the winter season (January), in the Mecsek Hills, next to Pécs, Hungary. Systolic blood pressure decreased after the trips both in late spring and in the winter. Based on changes in the expressions of CD69, an early activation marker, NKG2D, a major recognition receptor, perforin, granzyme B, and TIM-3, an inhibitory immune checkpoint molecule, on CD8+ cytotoxic T, NK, NKdim, NKbright, and NKT cells, we detected the stimulation of NKbright cells and activation of all examined immune cell subsets in the green season. In the winter, a slight activating and an interesting balancing effect regarding TIM-3 could be observed considering our finding that basal (pretest) TIM-3 expression by NK cells was significantly lower in the winter. Our work expands the knowledge on and potentials of forest medicine.
... Phytoncides significantly increase NK cell activity with a concomitant increase in the expression levels of perforin and granzyme B, crucial effector molecules in NK cellmediated cytotoxicity [36][37][38]. Furthermore, phytoncides have been observed to increase the number of CD56 molecules, which, along with CD107a, mark the activation of NK cells [39]. ...
Natural killer (NK) cells are lymphocytes that can directly destroy cancer cells. When NK cells are activated, CD56 and CD107a markers are able to recognize cancer cells and release perforin and granzyme B proteins that induce apoptosis in the targeted cells. In this study, we focused on the role of phytoncides in activating NK cells and promoting anticancer effects. We tested the effects of several phytoncide compounds on NK-92mi cells and demonstrated that α-pinene treatment exhibited higher anticancer effects, as observed by the increased levels of perforin, granzyme B, CD56 and CD107a. Furthermore, α-pinene treatment in NK-92mi cells increased NK cell cytotoxicity in two different cell lines, and immunoblot assays revealed that the ERK/AKT pathway is involved in NK cell cytotoxicity in response to phytoncides. Furthermore, CT-26 colon cancer cells were allografted subcutaneously into BALB/c mice, and α-pinene treatment then inhibited allografted tumor growth. Our findings demonstrate that α-pinene activates NK cells and increases NK cell cytotoxicity, suggesting it is a potential compound for cancer immunotherapy.
... The first experiment showed in vitro that phytoncides activate NK cell activity and augment NK cell granule content. 26 Then they confirmed this in peripheral blood lymphocytes of subjects submitted to a prospective trial of a 3-day, 2-night trip to the forest including three 2-h walks. 27 In a third casecontrol trial they demonstrated that the effect was not related to the walking tour, as they compared the rise in NK-cell activity after a 3-day tour to a small city with that after a 3-day tour to the forest. ...
Introduction
In light of the current COVID-19 pandemic, during which the world is confronted with a new, highly contagious virus that suppresses innate immunity as one of its initial virulence mechanisms, thus escaping from first-line human defense mechanisms, enhancing innate immunity seems a good preventive strategy.
Methods
Without the intention to write an official systematic review, but more to give an overview of possible strategies, in this review article we discuss several interventions that might stimulate innate immunity and thus our defense against (viral) respiratory tract infections. Some of these interventions can also stimulate the adaptive T- and B-cell responses, but our main focus is on the innate part of immunity. We divide the reviewed interventions into: 1) lifestyle related (exercise, >7 h sleep, forest walking, meditation/mindfulness, vitamin supplementation); 2) Non-specific immune stimulants (letting fever advance, bacterial vaccines, probiotics, dialyzable leukocyte extract, pidotimod), and 3) specific vaccines with heterologous effect (BCG vaccine, mumps-measles-rubeola vaccine, etc).
Results
For each of these interventions we briefly comment on their definition, possible mechanisms and evidence of clinical efficacy or lack of it, especially focusing on respiratory tract infections, viral infections, and eventually a reduced mortality in severe respiratory infections in the intensive care unit. At the end, a summary table demonstrates the best trials supporting (or not) clinical evidence.
Conclusion
Several interventions have some degree of evidence for enhancing the innate immune response and thus conveying possible benefit, but specific trials in COVID-19 should be conducted to support solid recommendations.
... Among the olfactive elements, long-lasting physiological health benefits were attributed to the inhalation of certain bioactive compounds residing in the forest atmosphere, including natural airborne microbiota and phytoncides, or biogenic volatile organic compounds (BVOCs), mainly monoterpenes (MTs), followed by sesquiterpenes [19]. For example, the MTs emitted by conifer trees were related to specific biological mechanisms, such as enhancing the numerosity and activity of natural killer cells (α-pinene and d-limonene) [20,21] and improving sleep duration and quality (α-pinene and 3-carene) [22]. ...
The prolonged lockdown imposed to contain the COrona VIrus Disease 19 COVID-19 pandemic prevented many people from direct contact with nature and greenspaces, raising alarms for a possible worsening of mental health. This study investigated the effectiveness of a simple and affordable remedy for improving psychological well-being, based on audio-visual stimuli brought by a short computer video showing forest environments, with an urban video as a control. Randomly selected participants were assigned the forest or urban video, to look at and listen to early in the morning, and questionnaires to fill out. In particular, the State-Trait Anxiety Inventory (STAI) Form Y collected in baseline condition and at the end of the study and the Part II of the Sheehan Patient Rated Anxiety Scale (SPRAS) collected every day immediately before and after watching the video. The virtual exposure to forest environments showed effective to reduce perceived anxiety levels in people forced by lockdown in limited spaces and environmental deprivation. Although significant, the effects were observed only in the short term, highlighting the limitation of the virtual experiences. The reported effects might also represent a benchmark to disentangle the determinants of health effects due to real forest experiences, for example, the inhalation of biogenic volatile organic compounds (BVOC).
... Scents and other substances in the air of natural environments are also likely to play an important role in restorative processes associated with experiences in nature. For instance, studies have demonstrated the effect of phytoncides, essential oils emitted by plants also referred to as "aroma of the forest", on stress hormones and the immune function [32][33][34]. The reliance on vision would imply that visually impaired individuals are unable to experience restoration in nature, and no evidence exists to suggest this. ...
Natural environments have been shown to trigger psychological and physiological restoration in humans. A new framework regarding natural environments restorative properties is proposed. Conditioned restoration theory builds on a classical conditioning paradigm, postulating the occurrence of four stages: (i) unconditioned restoration, unconditioned positive affective responses reliably occur in a given environment (such as in a natural setting); (ii) restorative conditioning, the positive affective responses become conditioned to the environment; (iii) conditioned restoration, subsequent exposure to the environment, in the absence of the unconditioned stimulus, retrieves the same positive affective responses; and (iv) stimulus generalization, subsequent exposure to associated environmental cues retrieves the same positive affective responses. The process, hypothetically not unique to natural environments, involve the well-documented phenomenon of conditioning, retrieval, and association and relies on evaluative conditioning, classical conditioning, core affect, and conscious expectancy. Empirical findings showing that restoration can occur in non-natural environments and through various sensory stimuli, as well as findings demonstrating that previous negative experience with nature can subsequently lower restorative effects, are also presented in support of the theory. In integration with other existing theories, the theory should prove to be a valuable framework for future research.
... The authors reported that, although these activities are not limited to forest bathing and can be exploited through skin applications or oral intake of essential oils, the contact during forest bathing may be safer, although less beneficial [4]. In any case, only a small number of preclinical studies have investigated the role of total extracts of forest BVOCs: volatile compounds extracted from hinoki wood essential oil have been reported to increase in vitro the natural killer (NK) cell activity by enhancing the expression of cytolytic enzymes [64]; also, an extract obtained from pinecones has been found to protect bovine mammary epithelial cells, stimulated with lipopolysaccharide (LPS), from oxidative stress after downregulating cyclooxygenase-2 (COX-2) expression [65]. On the other hand, single terpenes (α-phellandrene, 1,8 cineole, linalool, and β-caryophyllene) have been successfully used as pre-treatment to reduce the levels of interleukins, TNF-α, and iNOS in cellular and animal inflammatory-induced models [66][67][68][69]. ...
The aim of this research work is to analyze the chemistry and diversity of forest VOCs (volatile organic compounds) and to outline their evidence-based effects on health. This research work was designed as a narrative overview of the scientific literature. Inhaling forest VOCs like limonene and pinene can result in useful antioxidant and anti-inflammatory effects on the airways, and the pharmacological activity of some terpenes absorbed through inhalation may be also beneficial to promote brain functions by decreasing mental fatigue, inducing relaxation, and improving cognitive performance and mood. The tree composition can markedly influence the concentration of specific VOCs in the forest air, which also exhibits cyclic diurnal variations. Moreover, beneficial psychological and physiological effects of visiting a forest cannot be solely attributed to VOC inhalation but are due to a global and integrated stimulation of the five senses, induced by all specific characteristics of the natural environment, with the visual component probably playing a fundamental role in the overall effect. Globally, these findings can have useful implications for individual wellbeing, public health, and landscape design. Further clinical and environmental studies are advised, since the majority of the existing evidence is derived from laboratory findings.
... Among the olfactive elements, long lasting physiological health benefits were attributed to the inhalation of certain bioactive compounds residing in the forest atmosphere, including natural airborne microbiota and phytoncides, or biogenic volatile organic compounds (BVOCs), mainly monoterpenes (MTs), followed by sesquiterpenes [14]. For example, the MTs emitted by conifer trees were related to specific biological mechanisms, such as enhancing the numerosity and activity of natural killer cells (-pinene and d-limonene) [15,16], and improving sleep duration and quality (-pinene and 3-carene) [17]. ...
The prolonged lockdown imposed to contain the COVID-19 pandemic prevented many people from direct contact with nature and greenspaces, raising alarms for a possible worsening of mental health. This study investigates the effectiveness of a simple and affordable remedy for improving psychological well-being, based on audio-visual stimuli brought by a short computer video showing forest environments, with an urban video as a control. Randomly selected participants were assigned the forest or urban video, to look at and listen early in the morning, and filled questionnaires. In particular, the State-Trait Anxiety Inventory (STAI) Form Y, collected in baseline condition and at the end of the study, and the Part II of the Sheehan Patient Rated Anxiety Scale (SPRAS), collected every day immediately before and after watching the video. The virtual exposure to forest environments showed effective to reduce perceived anxiety levels in in people forced by lockdown in limited spaces and environmental deprivation. Although significant, the effects were observed only in the short term, highlighting the limitation of the virtual experiences. The reported effects might also represent a benchmark to disentangle the determinants of health effects due to real forest experiences, for example, the inhalation of biogenic volatile organic compounds (BVOC).
It has long been known that the forest, as a "feel-good space," has a positive effect on human well-being. In recent years, medical studies have also been conducted on this subject. However, there are only a few studies with a sufficient number of cases and valid statistics.
The article describes the various health effects of forest visits on humans, such as physiological and psychological changes, although the mechanisms of action are often still unclear. The field of forest and health research is still in its infancy. A cooperation between the chairs "Forest and Environmental Policy" (TUM) and "Public Health and Health Services Research (IBE)" (LMU) will deal intensively with this topic in the coming years.
This article argues for a mutation in how mental health is conceived in the early twenty-first century. In this mutation, physical environments, in the form of homes, workplaces, and streetscapes, are understood as central to the production and maintenance of good mental health. Much writing on this topic has taken place within a rhetorical division between stereotypically urban buildings or spaces (tower blocks, for example), which are said to be harmful to the human mind, and idealized rural or green spaces, such as parks or small hamlets, understood to be psychologically restorative. This discourse, which has its roots in both cultural and scientific developments, has rendered mental disorder as, at least in part, a spatial problem—which is to say, as a problem that might be both understood through but also treated by spatial practices. The goal of the article is to establish the ground of this claim and to make some of its epistemic roots visible. The article begins with an ethnographic account of a contemporary intellectual movement aimed at populating urban spaces with trees in the name of global mental health. Then the discussion turns to a series of critical developments in the psychological and neurobiological sciences—the article demonstrates how these, in turn, are efflorescing into new links between the architectural and psychological sciences. The article shows how this scientific discussion is paralleled by developments in urban planning—Ebenezer Howard's program of the early twentieth century, set out in Garden Cities of To-Morrow, is taken as exemplary here. The article ends with a reading of Clive Barker's 1985 short story “The Forbidden” and of the film Candyman, which it gave rise to, whose shared sense of horror at the visceral consequences of failed urban experiments, I argue, should be read as a critical inflection point for the contemporary relationship between psychology and architecture.
Sacred natural sites are considered part of human beings and communities, consisting of unique medicinal plant species with specific therapeutic properties. Among the sacred trees, Nakshatravan comprises an impressive range of medicinal and aromatic plants, mainly trees, which may help as a source of readily available raw materials from temple premises for traditional medicine. Therefore, the review aims to analyze and compare the medicinal properties and volatile organic compounds (VOCs) of nakshatravan trees, which are associated with 27 nakshatras/constellations used in Vedic tradition since 2nd Century. Various scientific databases, such as Pubmed, Scopus, and Google Scholar, were used. The keywords such as constellation, nakshatravan trees, human health, sacred groves, volatile oil, essential oil, and influence on human diseases were used. The 27 nakshatravan trees belong to 20 families, of which the Moraceae family contributes five trees; Fabaceae, Papilonaceae, and Sapotaceae contribute two trees, whereas the remaining 16 family consists of 1 tree each. There are 92 different medicinal properties, and 132 Volatile Compounds (VCs) and 36 non-volatile compounds (NVCs) noted from 27 trees, which are reported from nakshatravan trees and used for the treatment and prevention of various human diseases. An innovative approach to conserving these plants diversity has been emerging as ‘Star Garden’ comprising imperative medicinal trees with several unique or common medicinal properties. This approach will facilitate establishing and maintaining important, unique medicinal tree species. In the present study, we have analyzed common and unique medicinal properties, volatile and non-volatile compounds of 27 nakshatravan trees, and their potential pharmacological values.
Die Ökopsychosomatik beschreibt die Wirkung von stofflichen sowie nicht stofflichen Stimulanzien aus Ökosystemen auf die psychische und somatische Gesundheit des Menschen. Sie erforscht die pathogenen und salutogenen Umwelt- und Natureinflüsse, um die daraus gewonnenen Erkenntnisse für die öffentliche Gesundheit sowie für die Therapie von Krankheitszuständen nutzbar zu machen. Im ökopsychosomatischen Paradigma wird der menschliche Organismus als eingebunden in einen evolutionsbedingten Funktionskreis mit seinen natürlichen Lebensräumen betrachtet. Der Mensch ist Teil der Biodiversität. Nicht nur Umweltschadstoffe wirken sich ungünstig auf Gesundheit und Genesungsaussichten aus, sondern auch die Durchbrechung des Funktionskreises durch Trennung von den Einflüssen intakter Ökosysteme. Die „Waldmedizin“ ist als evidenzbasiertes Beispiel der angewandten Ökopsychosomatik und Ökoimmunologie zu betrachten. Der Artikel gibt einen Überblick über das interdisziplinäre Feld der Ökopsychosomatik und Ökoimmunologie.
Shinrin-Yoku describes “bathing in the atmosphere of the forest”. This chapter is about the atmosphere of the forest. It is based on the special climatic factors of forests and their exchange with the environment and the overall atmosphere. We perceive and process the forest atmosphere with all our senses, which includes the structure of the forest and its aesthetics. All these individual elements of the forest atmosphere have concrete health-promoting or even therapeutic effects, which are also demonstrated.
W toczonych od wielu lat dyskusjach na temat roli lasów w bilansie węglowym Biosfery wysuwano argumenty odnoszące się do różnych okresów czasu, od dziesięcioleci po tysiąclecia. Teraz perspektywa czasowa, przynajmniej w Europie, została skonkretyzowana do trzech dziesięcioleci. Nie ma już zatem wielkiego znaczenia rozpatrywanie problemu, na ile stuleci pozostanie związany w biomasie dwutlenek węgla; ważne jest, czy pozostanie tam przez najbliższe dziesięciolecia, oraz ile go tam będzie. Stawia to w innym świetle argumenty odnoszące się do tego, czy dla poprawy bilansu węglowego w skali Biosfery lepiej jest pozostawiać stare lasy bez ingerencji, czy też może lepiej wycinać je i zastępować młodymi? Wycinanie starych lasów po to, żeby poprawić bilans węglowy, nie ma sensu w 30-letniej perspektywie. Młode lasy pochłoną to, co zostało wyemitowane przy wycinaniu starych, nie wcześniej niż za 50-70 lat, a i to przy założeniu, że duża część drewna pozyskanego przy wycinaniu starych lasów zostanie wbudowana w produkty o długim czasie trwania. Należy też pamiętać o tym, że lasy, przede wszystkim te o cechach naturalnych, pełnią kluczową rolę w utrzymaniu globalnej różnorodności biologicznej. Różnorodność biologiczna lasów jest rezultatem procesów ewolucyjnych toczących się w nich przez tysiące, a nieraz miliony lat, pod wpływem klimatu, ognia, konkurencji i zaburzeń. Tak zróżnicowane biologicznie układy stwarzają organizmom szansę na adaptację do stale zmieniających się warunków środowiskowych i zapewniają ciągłość procesów ekologicznych, gwarantujących trwałość lasów i zapewniających korzyści człowiekowi. Bogate w gatunki, zróżnicowane strukturalnie lasy nabierają więc szczególnie dużego znaczenia w dobie kryzysu klimatycznego, albowiem nie tylko efektywnie kumulują węgiel, ale też dają możliwość przetrwania gatunkom najlepiej adaptującym się do zmian klimatu i nasilających się wraz z nimi zaburzeń. Wraz ze wzrostem urbanizacji i świadomości ekologicznej społeczeństwa z roku na rok rośnie również znaczenie tych funkcji lasu, które nie wiążą się bezpośrednio z materialnymi korzyściami. Wśród nich są m. in. magazynowanie i cyrkulacja wody, regulacja klimatu, regulacja populacji szkodników i chorób, czy też niezbędne dla zdrowia psychicznego duchowe, rekreacyjne i intelektualne interakcje z przyrodą. Znaczenie tych ostatnich jest jeszcze słabo rozpoznane, ale wydaje się, że odgrywają dużą rolę zwłaszcza w otoczeniu większych miast oraz w regionach uznawanych za ostoje naturalności. Gospodarując w lesie, kształtując jego strukturę i skład gatunkowy, wpływamy zarówno na liczbę jak i na intensywność produkcyjnych i pozaprodukcyjnych funkcji lasu. Oczywiście potrzebujemy i będziemy potrzebować drewna, gdyż jest ono bardzo ważnym surowcem. Lepiej jednak nie pozyskiwać go w starych lasach, tylko w drzewostanach młodszych, a zwłaszcza plantacjach zakładanych na terenach obecnie bezleśnych. Plany KE zmierzające do objęcia ochroną 30% obszarów, w tym 10% ochroną ścisłą są milowym krokiem w kierunku efektywnej ochrony ekosystemów leśnych Europy, w tym najlepiej zachowanych, starych lasów. Potrzebujemy nowego podejścia do zarządzania lasami, które zminimalizuje rosnącą liczbę konfliktów na styku gospodarki leśnej i społeczeństwa.
Environmental neuroscience is a field which uses multiple scales of analysis to elucidate the ways in which the physical environment interacts with neural processing to affect behavior. One environment that is heavily studied by environmental neuroscientists is the natural environment and how interacting with more natural environments (e.g., a city park) may benefit psychological functioning. This multidisciplinary environmental neuroscience approach examines processes and factors that vary across temporal and spatial scales. Most research studies examining the effects of interacting with natural environments on individuals’ neural processing and behavior fall into what we term meso-scale studies, which consist of real or simulated nature exposure on the order of minutes to hours. These are typically laboratory studies which attempt to quantify the effects of nature in an experimental setting. Macro-scale studies examine the effects of nature/green space exposure on people across large populations (e.g., a city) over long durations (e.g., on the order of years). These studies are typically observational but speak to the ecological validity of the meso-scale studies. Micro-scale studies tend to examine the specific elements of natural environments that may lead to the psychological benefits of interacting with nature, such as the low-level visual and acoustic features of nature and how perceiving those features may lead to cognitive benefits. Though immense progress has already been made in these domains, we propose that rapid advancements will be made through the increased use of methods that can span temporal and spatial scales and with more rigorous neuroimaging research, which may identify the neural mechanisms which drive these behavioral effects. We conclude with a brief discussion for how adopting an environmental neuroscience perspective can be of value to other fields of research, such as urban planning and environmental conservation.
The current body of literature points monoterpenes as one of the determinant factors of the interaction between forests and human health. The present study aims at analyzing the monoterpene absorption by humans during a 2 -hs forest exposure in a Mediterranean holm oak forest focusing on the four most abundant monoterpene compounds: alpha-pinene, beta-pinene, alpha-phellandrene and limonene. Participants’ blood samples were collected before and after exposure to forest or urban environment (control). We conducted air and blood sampling using cartridges and head space method and determined the monoterpene compounds through CG-MS. We identified the four compounds in forest air during the experimental study being alpha-pinene the monoterpene with the greatest concentration. Results show no significant changes in monoterpene blood concentrations for the forest and control group. However, a negative significant relationship between absorption and baseline blood concentration of the most abundant forest air monoterpenes, alpha-pinene and beta-pinene, was found in individuals visiting the forest, i.e. higher absorption was found the lower the baseline blood concentration was. Although no significant lineal correlation could be spotted between the vital variables and the monoterpene absorption, we found significant correlations between the absorption of the monoterpene compounds. This attempt, first in a Mediterranean holm oak forest, can serve as a starting point and constitute a valuable contribution for further research in regard to experimental design and laboratory analysis.
The utilization of pesticides has increased for destroying pests and protecting crops in the agriculture field. Triazophos is a commonly used organophosphorous insecticide that causes alterations in haematological and histological parameters in fish. The present study was designed to evaluate the effect of triazophos induced innate and cell mediated immunotoxicity in freshwater teleost, Channa punctata. Fishes were exposed to triazophos at concentrations 5 and 10% of LC50 value for 10 and 20 days. Splenic and head kidney macrophage phagocytosis, nitric oxide production and superoxide production were assayed to evaluate the innate immunity. Cell-mediated immunity was measured through splenic and head kidney lymphocyte proliferation in presence of T and B cell mitogens. Results of the present study revealed that macrophage phagocytosis was significantly reduced after in vivo triazophos treatment. Differential suppressive effect of triazophos was also observed where mitogen induced splenic and head kidney lymphocyte proliferations were reduced after 10 and 20 days treatment. Concentration dependent effect of triazophos was observed in in vivo studies where the production of reactive oxygen and nitrogen intermediates were suppressed. This study describes the first investigation of the effect of triazophos on immune functions and will help to determine appropriate ecotoxicity and immunotoxicity in freshwater teleosts.
This book surveys state-of-the-art and prospective practices, methods and technologies in agri-food and forestry sectors to document the potential measurable improvements in areas of environmental management, food security, economic growth, social cohesion and human health at the local and global scale. With a focus on the ecosystems-resources-climate-food-health nexus as a framework towards achieving the UN Sustainable Development Goals applicable in these sectors, the book offers a portfolio of guidelines and standards that assesses the affordability, potential profitability and possible unintended consequences of interventions. The areas of intervention covered in the study include global and local forest resources management, safe wastewater reuse for irrigation, sustainable crop and plant protection (e.g. biopesticides, bioherbicides), carbon sequestration and emission reduction strategies, and safe processing methods for food and food waste (e.g. sustainable food preservatives and healthier food). The book is primarily intended for academics, professionals, and policymakers. The professional audience, including enterprises in the forestry, farming, food processing, healthcare and waste management sectors, will take advantage of the updated knowledge basis concerning the innovations in the respective practices, methods and technologies, including their feasibility, affordability and profitability, and policymakers will find useful the comprehensive review of these innovations which could be strategically promoted and deployed in the next decade, with the aim of achieving the UN Sustainable Development Goals.
This chapter reviews researches showing the great potential of non-timber use of forest products, in particular needles, bark, wood, and cones from conifer species, which are especially rich of essential micronutrients and could substantially contribute to their adequate intake in the human diet. The valorization of bioactive molecules through the extraction from residues of forest biomass, if integrated into wood industry processes, could add value to the wood processing chain, offsetting production costs, providing additional income that could be reinvested in reforestation or afforestation policies, while reducing waste and improving the human health. This chapter also explores the tremendous potential, so far largely underexploited, to improve human mental and physiological health due to the forest healing effects, which is an important emerging forest ecosystem service. The role of biogenic volatile organic compounds emitted by plants in the forest atmosphere is discussed, as an important determinant of long-lasting physiological health benefits, such as the immune-protective ones, deriving from exposure to the forest environment. Forest bathing and forest therapy practices are proposed as a win-win strategy to improve public health while achieving considerable healthcare savings, raise economic and social opportunities in remote areas, and contribute to sustainable forest management.
Triazophos is a commonly used organophosphate insecticide, which inhibits the acetylcholinesterase enzyme and causes paralysis and death of insects. Impact of the pesticides on immunity has scarcely been investigated, especially in fishes. The present study was designed to analyze the immunotoxic role of in vitro triazophos exposure to the leucocytes in freshwater teleost, Channa punctatus. Triazophos, at in vitro concentrations of 0.1, 0.5, and 1 µg ml⁻¹, was used to study leucocyte phagocytosis, superoxide production, nitrite release, and lymphocyte proliferation. Dose-dependent suppression of various immune responses was observed. Nitrite release and superoxide production by leucocytes were reduced in cultures incubated with triazophos. Mitogen-induced lymphocyte proliferation was significantly reduced at 0.5 and 1 µg ml⁻¹ but not at 0.1 µg ml⁻¹ concentration of pesticide. The biphasic suppressive effect was also discovered while evaluating phagocytic response. These investigations describe the effects of pesticide on immune responses in C. punctatus, which are helpful in understanding the immunotoxicity in fish. Substantially more researches are required to help design the measures to combat ecotoxicity in freshwater bodies.
It is clear that our health is also determined by our environment. This book discloses current knowledge (2020) of the main benefits of green spaces on human health. It also includes some unique initiatives that explore the binomial green and health. Finally, proposes strategies and tools to increase the "dose of nature" in health systems. A publication of DKV Seguros (Spanish health insurer) with the ISGlobal scientific review.
In this study, we used an irradiation system to investigate differences in the following: (1) impressionistic assessment of room environment; (2) effects on physical and psychological restorativeness; and (3) job satisfaction due to brief rests in a nursing home room with or without Komore-bi. Results showed that impressionistic assessment (SD/PRS) for each room environment was more positive with Komore-bi. Additionally, salivary amylase activity, a physical indicator, was significantly reduced; while the subjective feeling of restorativeness (ROS) and mood states (POMS), both psychological indicators, significantly improved in the room with Komore-bi. Furthermore, some statistical differences in job satisfaction were found in the presence or absence of Komore-bi. In other words, this experiment has shown that short exposure to the Komore-bi irradiation system might contribute to the physical and psychological recovery and increased job satisfaction among staff members.
Mice bearing the experimental murine renal cancer Renca can be successfully treated with some forms of immunotherapy. In the present study, we have investigated the molecular pathways used by NK and T cells to lyse Renca cells. Renca cells normally express low levels of Fas that can be substantially enhanced by either IFN-γ or TNF-α, and the combination of IFN-γ + TNF-α synergistically enhances cell-surface Fas expression. In addition, cells pretreated with IFN-γ and TNF-α are sensitive to lysis mediated by Fas ligand (FasL)-expressing hybridomas (dllS), cross-linking of anti-Fas Abs or soluble Fas (FasL). Lysis via Fas occurs by apoptosis, since Renca shows all the typical characteristics of apoptosis. No changes in levels of bcl-2 were observed after cytokine treatments. We also examined cell-mediated cytotoxic effects using activated NK cells and T cells from gld FasL-deficient mice, and perforin-deficient mice, as well as wild-type C57BL/6 and BALB/c mice. Interestingly, the granule-mediated pathway predominated in killing of Renca by activated NK cells, while the Fas/FasL pathway contributed significantly to cell-mediated killing of Renca by activated T cells. These results suggest that killing of Renca tumor cells by immune effector cells can occur by both granule and Fas-mediated cytotoxicity. However, for the Fas-mediated pathway to function, cell surface levels of Fas need to be increased beyond a critical threshold level by proinflammatory cytokines such as IFN-γ and TNF-α.
Using a subtractive hybridization procedure we have constructed a cDNA library enriched for sequences present in functional human T cell lines, but not in human EBV-transformed B cell lines. We have isolated a cDNA clone, AH2-519, representing a novel gene, designated 519. This novel gene is expressed in functional human cytolytic and Th cell lines but not in a variety of other cell lines, including several long-term human T cell tumor lines. The expression of gene 519 is inducible in cultures of normal human PBL using antigenic or mitogenic stimulation. Neither the DNA sequence determined from a full-length cDNA clone overlapping with clone AH2-519 nor the amino acid sequence of its predicted protein product has significant homology to published sequences in the GenBank or NBRF databases. The restricted expression of gene 519 suggests that its gene product is involved in the growth and/or differentiation of normal T cells. The data also show that normal, nontransformed, functional T cells express gene products that can not be readily identified in long-term tumor lines of the same cell lineage.
Two molecular mechanisms of T cell-mediated cytotoxicity, one perforin-based, the other Fas-based, have been demonstrated.
To determine the extent of their contribution to T cell-mediated cytotoxicity, a range of effector cells from normal control
or perforin-deficient mice were tested against a panel of target cells with various levels of Fas expression. All cytotoxicity
observed was due to either of these mechanisms, and no third mechanism was detected. Thus, the perforin- and Fas-based mechanisms
may account for all T cell-mediated cytotoxicity in short-term in vitro assays.
Cytolytic T lymphocytes (CTLs) kill intracellular pathogens by a granule-dependent mechanism. Granulysin, a protein found
in granules of CTLs, reduced the viability of a broad spectrum of pathogenic bacteria, fungi, and parasites in vitro. Granulysin
directly killed extracellularMycobacterium tuberculosis, altering the membrane integrity of the bacillus, and, in combination with perforin, decreased the viability of intracellular
M. tuberculosis. The ability of CTLs to kill intracellular M. tuberculosis was dependent on the presence of granulysin in cytotoxic granules, defining a mechanism by which T cells directly contribute
to immunity against intracellular pathogens.
CTL and NK cells use two distinct cytocidal pathways: 1) perforin and granzyme based and 2) CD95L/CD95 mediated. The former requires perforin expression by the effectors (CTL or NK), whereas the latter requires CD95 (Fas/APO-1) expression by the target. We have investigated how these two factors contribute to tumor immune surveillance by studying the immunity of perforin-deficient mice against the progressor C57BL/6 Lewis lung carcinoma 3LL, which expresses no CD95 when cultured in vitro. Unexpectedly, the results indicated that the perforin-independent CD95L/CD95 pathway of CTL/NK plays a role in acting against D122 and Kb39.5 (39.5) high and low metastatic sublines, respectively, derived from the 3LL tumor. Although no membrane-bound CD95 was detected on cultured D122 and 39. 5 cells, surface CD95 expression on both D122 and 39.5 was considerably up-regulated when the tumors were grown in vivo. A similarly enhanced expression of CD95 was observed with three additional tumors; LF-, BW, and P815, injected into syngeneic and allogeneic mice. The finding of up-regulated CD95 expression on tumor cells placed in vivo suggests that a CD95-based mechanism plays a role in tumor immunity at early stages of tumor growth. Consequently, the progressive down-regulation of CD95 expression during tumor progression may indeed be an escape mechanism as previously reported. Together, these results suggest a role for CD95-dependent, perforin-independent immunity against certain tumors.
The cytotoxic T lymphocyte protease granzyme A induces caspase-independent cell death in which DNA single-strand nicking is
observed instead of oligonucleosomal fragmentation. Granzyme A is a specific tryptase that concentrates in the nucleus of
targeted cells and synergistically enhances DNA fragmentation induced by the caspase activator granzyme B. Here we show that
granzyme A treatment of isolated nuclei enhances DNA accessibility to exogenous endonucleases.In vitro and after cell loading with perforin, GrnA completely degrades histone H1 and cleaves core histones into ∼16-kDa fragments.
Histone digestion provides a mechanism for unfolding compacted chromatin and facilitating endogenous DNase access to DNA during
T cell and natural killer cell granule-mediated apoptosis.
The effects of chiral fragrances (enantiomers of limonene and carvone) on the human autonomic nervous system (ANS) and on self-evaluation were studied in 20 healthy volunteers. Each fragrance was administered to each subject by inhalation using an A–A–B design. Individuals were tested in four separate sessions; in one session one fragrance was administered. ANS parameters recorded were skin temperature, skin conductance, breathing rate, pulse rate, blood oxygen saturation and systolic
as well as diastolic blood pressure. Subjective experience was assessed in terms of mood, calmness and alertness on visual analog scales. In addition, fragrances were rated in terms of pleasantness, intensity and stimulating property. Inhalation of (+)-limonene led to increased systolic blood pressure, subjective alertness and restlessness. Inhalation of (–)-limonene caused an increase in systolic blood pressure but had no effects on psychological parameters. Inhalation of (–)-carvone caused increases in pulse rate, diastolic blood pressure and subjective restlessness. After inhalation of (+)-carvone increased levels of
systolic as well as diastolic blood pressure were observed. Correlational analyses revealed that changes in both ANS parameters and self-evaluation were in part related to subjective evaluation of the odor and suggest that both pharmacological and psychological mechanisms are involved in the observed effects. In conclusion, the present study indicates that: (i) prolonged inhalation of fragrances influences ANS parameters as well as mental and emotional conditions; (ii) effects of fragrances are in part based on subjective evaluation of odor; (iii) chirality of odor molecules seems to be a central factor with respect to the
biological activity of fragrances.
We investigated the effects of fragrance inhalation on sympathetic activity in normal adult subjects using both power spectral analysis of blood pressure fluctuations and measurement of plasma catecholamine levels. Fragrance inhalation of essential oils, such as pepper oil, estragon oil, fennel oil or grapefruit oil, resulted in 1.5- to 2.5-fold increase in relative sympathetic activity, representing low frequency amplitude of systolic blood pressure (SBP-LF amplitude), compared with inhalation of an odorless solvent, triethyl citrate (P<0.05, each). In contrast, fragrance inhalation of rose oil or patchouli oil caused a 40% decrease in relative sympathetic activity (P<0.01, each). Fragrance inhalation of pepper oil induced a 1.7-fold increase in plasma adrenaline concentration compared with the resting state (P = 0.06), while fragrance inhalation of rose oil caused a 30% decrease in adrenaline concentration (P<0.01). Our results indicate that fragrance inhalation of essential oils may modulate sympathetic activity in normal adults.
Granulysin, a molecule present in the granules of CTL and NK cells, is cytolytic against microbes and tumors. Granulysin induces apoptosis of mammalian cells by damaging mitochondria and causing the release of cytochrome c and apoptosis-inducing factor, resulting in DNA fragmentation. Here we show that Ca2+ and K+ channels as well as reactive oxygen species are involved in granulysin-mediated Jurkat cell death. The Ca2+ channel blockers, nickel and econazole, and the K+ channel blockers, tetraethylammonium chloride, apamin, and charybdotoxin, inhibit the granulysin-induced increase in intracellular Ca2+ ([Ca2+](i)), the decrease in intracellular K+, and apoptosis. Thapsigargin, which releases Ca2+ from the endoplasmic reticulum, prevents a subsequent granulysin-induced increase in [Ca2+](i) in Jurkat cells, indicating that the initial increase in [Ca2+](i) is from intracellular stores. The rise in [Ca2+](i) precedes a decrease in intracellular K+, and elevated extracellular K+ prevents granulysin-mediated cell death. In granulysin-treated cells, electron transport is uncoupled, and reactive oxygen species are generated. Finally, an increase in intracellular glutathione protects target cells from granulysin-induced lysis, indicating the importance of the redox state in granulysin-mediated cell death.
Using a subtractive hybridization procedure we have constructed a cDNA library enriched for sequences present in functional human T cell lines, but not in human EBV-transformed B cell lines. We have isolated a cDNA clone, AH2-519, representing a novel gene, designated 519. This novel gene is expressed in functional human cytolytic and Th cell lines but not in a variety of other cell lines, including several long-term human T cell tumor lines. The expression of gene 519 is inducible in cultures of normal human PBL using antigenic or mitogenic stimulation. Neither the DNA sequence determined from a full-length cDNA clone overlapping with clone AH2-519 nor the amino acid sequence of its predicted protein product has significant homology to published sequences in the GenBank or NBRF databases. The restricted expression of gene 519 suggests that its gene product is involved in the growth and/or differentiation of normal T cells. The data also show that normal, nontransformed, functional T cells express gene products that can not be readily identified in long-term tumor lines of the same cell lineage.
More than 5000 passengers on Tokyo subway trains were injured by the nerve gas, sarin and its by-products. Analysis of phosphor-carrying metabolites of sarin and its by-products in urine samples from the victims suggested that they were exposed not only to sarin, but also by-products generated during sarin synthesis, i.e. diisopropyl methylphosphonate (DIMP) and diethyl methylphosphonate (DEMP). We suspected genetic after-effects due to sarin by-products, thus, we checked the frequency of sister chromatid exchange (SCE) and found that SCE was significantly higher in the victims than in a control group, and that DIMP and DEMP significantly induced human lymphocyte SCE in vitro. In the present study, to explore whether DIMP and DEMP, which induced a high frequency of SCE of lymphocytes, also affected the lymphocyte functions, we examined the effect of DIMP and DEMP on splenic natural killer (NK) and splenic cytotoxic T lymphocyte (CTL) activity in mice, and NK activity of human lymphocytes in vitro. We found that DIMP and DEMP significantly inhibited NK and CTL activity in a dose-dependent manner. The inhibition induced by DIMP was stronger than that by DEMP. The effect of DIMP and DEMP on the splenic NK activity of mice was stronger than on the splenic CTL activity, and the human lymphocytes is more sensitive to DIMP and DEMP than the splenocytes of mice.
The aim of this study was to determine the effects of olfactory stimulation on immunological and behavioral states in mice. Anti-SRBC (IgM) plaque forming cell (PFC) count and spontaneous running activity (SRA) were measured to demonstrate the effects of exposure to a given fragrance. The decreased PFC count and thymic involution induced by high pressure stress in mice were recovered after exposing the stressed mice to the fragrance continuously for 4 days after the stress was given. The PFC and SRA also appeared to be maintained at normal levels by oflactory stimulation with the fragrance for 24 hrs after the given stress. The immunological suppression induced by high pressure stress was considered to be caused by the induction and activation of suppressor cells. However, exposure to the fragrance after the stress did not enhance suppressor activity. The restoration of the stress-induced immune suppression by olfactory stimulation was blocked by procain administration onto the olfactory cells.
Perforin is one of the cytolytic factors present in the cytoplasmic granules of mouse cytotoxic T lymphocytes and natural killer cells. We have determined the sequence of the N-terminal amino acids of perforin purified from a mouse natural killer cell line, and, by using oligonucleotide probes corresponding to the amino acid residues, we have identified a complementary DNA encoding perforin from the cDNA library of a mouse cytotoxic T lymphocyte clone. As predicted from the functional similarities between perforin and the ninth component of the serum cytolytic system, complement (C9) (refs 4-8), the deduced primary structure of perforin has homology with C9 at their respective functionally conserved regions. We find that perforin is only expressed in killer cell lines, and not in helper T lymphocytes or other tumour cells tested. Thus we have provided direct molecular evidence that a killer-cell-specific protein evolutionally linked to C9 is involved in cell-mediated cytolysis.
The recent generation of perforin knock-out mice has demonstrated a crucial role for the pore-forming perforin in cytolytic T-lymphocyte (CTL)-mediated cytolysis. Perforin-deficient mice failed to clear lymphocytic choriomeningitis virus in vivo, yet substantial killing activity still remained in perforin-free CTLs in vitro, indicating the presence of (a) further lytic pathway(s). Fas is an apoptosis-signalling receptor molecule on the surface of a number of different cells. Here we report that both perforin-deficient and Fas-ligand-deficient CTLs show impaired lytic activity on all target cells tested. The killing activity was completely abolished when both pathways were inactivated by using target cells from Fas-receptor-deficient lpr mice and perforin-free CTL effector cells. Fas-ligand-based killing activity was triggered upon T-cell receptor occupancy and was directed to the cognate target cell. Thus, two complementary, specific cytotoxic mechanisms are functional in CTLs, one based on the secretion of lytic proteins and one which depends on cell-surface ligand-receptor interaction.
Cytotoxic lymphocytes mediate immunity against viruses and surveillance against neoplastic transformation. They kill target cells by multiple mechanisms, but utilize a pore-forming protein, perforin, and a family of serine proteinases as their principal means of inflicting cell death. Recent studies have demonstrated that perforin and serine proteinases synergistically trigger an endogenous pathway of apoptosis resulting in dissolution of the target cell nuclear membrane and DNA fragmentation. These changes may be secondary to inappropriate activation of p34cdc2 kinase and the subsequent derangement of cell cycle control. As discussed by Mark Smyth and Joseph Trapani, the immediate molecular targets of perforin/granzyme-mediated apoptosis are still unclear, though candidate molecules with homology to cell death gene products from primitive organisms are currently under close scrutiny.
The cell line described here was established for a 50-year-old male patient with rapidly progressive non-Hodgkin's lymphoma whose marrow was diffusely infiltrated with large granular lymphocytes (LGL). Immunophenotyping of marrow blasts and peripheral lymphocytes was positive for CD56, CD2 and CD7, and negative for CD3. Cytotoxicity of peripheral blood mononuclear cells at an effector:target (E:T) cell ratio of 50:1 was 79% against K562 cells and 48% against Daudi cells. To establish the line, cells from the peripheral blood were placed into enriched alpha medium containing 12.5% fetal calf serum, 12.5% horse serum, 10-4 M β-mercaptoethanol and 10-6 M hydrocortisone. Growth of the line (termed NK-92) is dependent on the presence of recombinant IL-2 and a dose as low as 10 U/ml is sufficient to maintain proliferation. Conversely, cells die within 72 h when deprived of IL-2; IL-7 and IL-12 do not maintain long-term growth, although IL-7 induces short-term proliferation measured by 3H-thymidine incorporation. None of the other cytokines tested (IL-1α, IL-6, TNF-α, IFN-α, IFN-γ) supported growth of NK-92 cells which have the following characteristics: surface marker positive for CD2, CD7, CD11a, CD28 CD45, CD54, CD56(bright), surface marker negative for CD1, CD3, CD4, CD5, CD8, CD10, CD14, CD16, CD19, CD20, CD23, CD34, HLA-DR. DNA analysis showed germline configuration for T-cell receptor β and γ genes. CD25 (p55 IL-2 receptor) is expressed on about 50% of all cells when tested at 100 U/ml of IL-2 and its expression correlates inversely with the IL-2 concentration. The p75 IL-2 receptor is expressed on about half of the cells at low density irrespective of the IL-2 concentration. NK-92 cells kill both K562 and Daudi cells very effectively in a 4 h51-chromium release assay (84 and 86% respectively, at an E:T cell ratio of 5:1). The cell line described here thus displays characteristics of activated NK-cells and could be a valuable tool to study their biology.
Perforin-deficient mice have been generated by homologous recombination to determine whether the effects of CD8+ cytolytic T cells and natural killer cells are mediated by pore formation involving perforin. These mice are viable and fertile and have normal numbers of CD8+ T cells and natural killer cells which do not lyse virus-infected or allogeneic fibroblasts or natural killer target cells in vitro. The mice fail to clear lymphocytic choriomeningitis virus and they eliminate fibrosarcoma tumour cells with reduced efficiency. Perforin is therefore a key effector molecule for T-cell- and natural killer-cell-mediated cytolysis.
In our previous experiments on animals evidence was found that citrus fragrance can restore the stress-induced immunosuppression, suggesting that citrus fragrance may have an effect on restoring the homeostatic balance. Since a dysregulation of the neuroendocrine and immune function is thought to be associated with psychosomatic or psychiatric disorders an attempt was made to restore their mental health by stimulation of one of the sensory systems. Fragrance (citrus was our choice) which comforts through stimulation of the olfactory system was applied to depressive patients. It was given to 12 depressive subjects and the results indicated that the doses of antidepressants necessary for the treatment of depression could be markedly reduced. The treatment with citrus fragrance normalized neuroendocrine hormone levels and immune function and was rather more effective than antidepressants.
The release of cytotoxic granule contents by cytotoxic T lymphocytes triggers apoptotic target cell death. Cytotoxic granules contain a pore-forming protein, perforin, and a group of serine proteases called granzymes. We expressed human granzyme A in bacteria as a proenzyme capable of in vitro activation by enterokinase. The recombinant activated enzyme has catalytic activity against substrates with Arg, preferably, or Lys at the P1 position, comparable to trypsin. An enzymatically inactive recombinant granzyme A, with the active site Ser mutated to Ala, was produced and used with affinity chromatography to identify potential substrates. Two granzyme A-binding cytoplasmic proteins of molecular mass 33 and 44 kDa were isolated and identified by tryptic fragment sequencing as PHAP I and II, ubiquitous putative HLA-associated proteins, previously coisolated by binding to an HLA class II peptide. PHAP II forms an SDS-stable complex with recombinant mutant granzyme A and coprecipitates with it from cytoplasmic extracts. PHAP II, either purified or in cell lysates, is cleaved by the recombinant enzyme at nanomolar concentrations to a 25-kDa fragment. PHAP II begins to be degraded within minutes of initiation of cytotoxic T lymphocyte attack. PHAP I and II are candidate participants in the granzyme A pathway of cell-mediated cytotoxicity.
To study the effects of perfume and phytoncid on GABAA receptors, ionotropic GABAA receptors were expressed in Xenopus oocytes by injecting mRNAs that had been prepared from rat whole brain. Essential oil, perfume and such phytoncid as leaf alcohol, hinokitiol, pinene, eugenol, citronellol and citronellal potentiated the response in the presence of GABA at low concentrations (10 and 30 microM), possibly because they bound to the potentiation-site in GABAA receptors and increased the affinity of GABA to the receptors. Since it is known that the potentiation of GABAA receptors by benzodiazepine, barbiturate, steroids and anesthetics induces the anxiolytic, anticonvulsant and sedative activity or anesthetic effect, these results suggest the possibility that the intake of perfume or phytoncid through the lungs, the skin or the intestines modulates the neural transmission in the brain through ionotropic GABAA receptors and changes the frame of the human mind, as alcohol or tobacco does.
NK-92 is a highly cytotoxic natural killer (NK) tumor cell line that possesses properties that make it an excellent candidate for adoptive cellular immunotherapy. However, the cytotoxicity of NK cells is dependent on cytokines such as interleukin 2 (IL-2). Although NK-92 cells maintain cytotoxicity for a time after withdrawal of IL-2, clinical use will probably require prolonged treatment with fully activated cells to eliminate disease effectively. The ability to support cytotoxic cells with exogenously administered IL-2 is limited by associated toxicity. Therefore, we describe the transfection of the IL-2-dependent NK-92 cell line with human IL-2 (hIL-2) cDNA by particle-mediated gene transfer to create two IL-2-independent variants, NK-92MI and NK-92 CI, and describe their characterization and comparison with parental cells. Both variants were shown to contain, express, and synthesize the hIL-2 cDNA. IL-2 synthesis was higher in NK-92MI cells compared with NK-92CI cells, with no expression in parental cells. Functionally, the cytotoxicity of all three cell lines was similar and coincubation with IL-2-independent variants did not affect hematopoietic progenitor cells. NK-92MI and NK-92CI cells were more radiosensitive than NK-92 cells, with proliferation inhibited at lower radiation doses and increased morality and decreased cytotoxicity compared with parental cells. Data presented here show that we have created by particle-mediated gene transfer two IL-2-independent variants of NK-92 that are identical to parental cells in virtually all respects, including high cytotoxic activity. The nonviral transfection of these cells makes them suitable for clinical applications. These IL-2-independent cells should allow prolonged treatment with fully active natural killer cells without the need for exogenous IL-2 support.
Granulysin is a newly described lytic molecule expressed by CTL and NK cells. Three mRNA (519, 520, and 522) and two protein products of 15 and 9 kDa are encoded by the granulysin gene. Stable transfectants overexpressing the predominate 520 mRNA were generated to determine the protein products originating from the translation of this message. A transfectant of the NK cell tumor YT overexpressed both 15 and 9 kDa proteins while a transfectant of the T cell tumor HuT78 produced mainly 15 kDa granulysin. Thus the 520 mRNA is sufficient for production of both 15 and 9 kDa granulysin. 9 kDa granulysin accumulated via post-translational processing of 15 kDa protein and was present intracellularly but not in the cell culture supernatant, indicating specific retention of the 9 kDa protein. An inhibitor of granule acidification, concanamycin A, blocked the processing of 15 kDa granulysin to the 9 kDa form. A deduced structural difference between the two forms of the protein and a decrease in lytic activity of 9 kDa granulysin at granule pH suggest two mechanisms by which a granulysin expressing cell is protected from autolysis during the biosynthesis of this potentially harmful molecule.
Cytotoxic T lymphocytes (CTL) induce apoptosis by engaging death receptors or by exocytosis of cytolytic granules containing granzyme (Gzm) proteases and perforin. The lamins, which maintain the structural integrity of the nuclear envelope, are cleaved by caspases during caspase-mediated apoptosis. Although death receptor engagement and GzmB activate caspases, CTL also induce apoptosis during caspase blockade. Both GzmA and GzmB directly and efficiently cleave laminB in vitro, in situ in isolated nuclei and in cells loaded with perforin and Gzms, even in the presence of caspase inhibitors. LaminB is cleaved by GzmA at concentrations of 3 nM, but GzmB is 50 times less active. GzmA cuts laminB at R392; GzmB cuts at the caspase VEVD231 site. Characteristic laminB fragments generated by Gzm proteolysis also are observed during CTL lysis, even in the presence of caspase inhibitors or in cells overexpressing bcl-2. Lamins A/C are direct substrates of GzmA, but not GzmB. GzmA and GzmB therefore directly target critical caspase substrates in caspase-resistant cells.
We have previously found that diisopropyl methylphosphonate, an organophosphorus by-product generated during sarin synthesis in the Tokyo sarin disaster, significantly inhibited natural killer (NK) and cytotoxic T lymphocyte (CTL) activities. In the present study, to investigate whether organophosphorus pesticides (OPs) also affect NK and CTL activities, we firstly examined the effect of five OPs on human NK activity, and then the effect of Dimethyl 2,2-dichlorovinyl phosphate (DDVP), an OP on murine splenic NK, CTL and lymphokine-activated killer (LAK), and human LAK activities in vitro. To explore the underlying mechanism of decreased NK activity, we also investigated the effect of 4-(2-aminoethyl) benzenesulfonyl fluoride-HCl (p-ABSF), an inhibitor of serine proteases on NK, LAK and CTL activities, and the effect of DDVP on the activity of granzymes (serine proteases). We found that OPs significantly decreased human NK activity in a dose-dependent manner, but the degree of decrease in NK activity differed among the OPs investigated, and that DDVP significantly decreased NK, LAK and CTL activities in a dose-dependent manner, but the degree of decrease in these activities differed. p-ABSF showed a similar inhibitory pattern to DDVP, and had an additive inhibitory effect with DDVP on NK, LAK and CTL activities. We also found that DDVP significantly inhibited granzyme activity in a dose-dependent manner. These findings indicate that OPs significantly decrease NK, LAK and CTL activities in vitro via granzyme inhibition.
Natural killer (NK), lymphokine-activated killer (LAK) and cytotoxic T lymphocyte (CTL) cells induce target cell death by two main mechanisms, the perforin/granzyme pathway and the Fas-ligand (FasL)/Fas pathway. We have previously found that organophosphorus pesticides significantly inhibit human and murine NK, LAK and CTL activities and that this inhibition is partially mediated by the inhibition of granzymes. We asked here whether organophosphorus pesticides also affect the FasL/Fas pathway by using perforin-knockout (PKO) mice. Thus, we examined the effect that dimethyl 2,2-dichlorovinyl phosphate (DDVP), an organophosphorus pesticide has on NK, CTL and LAK activities of PKO mice in vitro using the Fas antigen-positive YAC-1 cell as a target in the present study. We found that DDVP significantly decreased NK, CTL and LAK activities in a dose-dependent manner, and that the CTL and LAK activities of PKO mice were significantly blocked by anti-FasL antibody, suggesting that DDVP and anti-FasL antibody have the same/similar mechanism of inhibiting LAK and CTL activities. We further found that DDVP decreases the expression of Fas antigen on YAC-1 cells, and the expression of FasL on LAK cells in a dose-dependent manner, respectively. Taken together, these findings indicate that the DDVP-induced inhibition of NK, LAK and CTL activities in PKO mice is mediated by the impairment of the FasL/Fas pathway.
1. Phytoncides are volatile substances released mainly from trees. We studied whether phytoncides can reduce stress responses in stroke-prone spontaneously hypertensive rats (SHRSP).
2. Under the restraint stress, SHRSP exposed to phytoncides showed lower blood pressure than those without the exposure (186.8 ± 3.9 vs 207.7 ± 3.4 mmHg, respectively, P < 0.01 by Student's t-test).
3. Consistent with the observation above, the plasma concentration of catecholamines under the restraint stress was lower in the phytoncides group than in the control group.
4. Based on these results, we concluded that phytoncides reduced the cardiovascular response to restraint stress in SHRSP.
Natural killer (NK), lymphokine-activated killer (LAK) and cytotoxic T lymphocyte (CTL) cells kill target cells by the directed release of cytolytic granules that contain perforin, granzymes and granulysin. We previously have found that dimethyl 2,2-dichlorovinyl phosphate (DDVP), an organophosphorus pesticide significantly inhibited NK, LAK and CTL activities via the inhibition of granzyme activity. To further explore the mechanism of organophosphorus pesticide-induced inhibition of cell-mediated cytolysis, we asked here whether organophosphorus pesticides affect the expression of perforin, granzyme and granulysin in NK cells. We used NK-92CI cell, an interleukin-2 (IL-2) independent human NK cell line. We confirmed that NK-92CI cells express CD56 surface marker, perforin, granzyme A and granulysin by flow cytometry and immunofluorescence microscope, and that it is highly cytotoxic to K562 cells in chromium release assay. We found that DDVP significantly decreases the expression of perforin, granzyme A and granulysin in NK-92CI cells in a dose-dependent manner. Immunocytochemical results showed that DDVP significantly decreases perforin, granzyme A and granulysin positive granules in NK-92CI cell, which may be due to the degranulation. We also found that DDVP have a modest, but a significant inhibitory effect on the transcription of mRNA of perforin, granzyme A and granulysin.
Granulysin is a cytolytic granule protein of natural killer (NK) cells and cytotoxic T lymphocytes (CTL) with a broad range of antimicrobial and tumoricidal activities. Two molecular forms of granulysin, the 15-kDa precursor and 9-kDa mature form, are produced in these cells. In this study, we developed monoclonal antibodies against granulysin and found that the 15-kDa granulysin is spontaneously secreted by peripheral blood NK and T cells via a non-granule exocytotic pathway. When NK cells killed the target cells, the released granulysin levels in culture supernatants significantly increased through the granule exocytosis. The granulysin protein was found in the sera of healthy individuals at an average concentration of 3.7 +/- 3.2 ng/ml (age 0-99 years, n=244). The serum levels of granulysin were transiently highly elevated among patients with acute viral infections. In addition, the serum granulysin levels in patients with severe immunodeficiency treated bycell therapy fluctuated proportionately to the improvement of other immunological parameters. Our results suggest that granulysin is well associated with diverse activities of NK cells and CTL in physiological and pathological settings and could be a useful novel serum marker to evaluate the overall status of host cellular immunity.
Granulysin, a molecule expressed by human natural killer cells and activated T lymphocytes, exhibits cytolytic activity against a variety of microbes and tumors. Progress in understanding the structure, function and clinical relevance of granulysin over the past year encompasses three main areas: first, the solution of its crystal structure, providing new insights into its potential mechanism of target cell damage; second, inhibition of its function with small interfering RNA, indicating its relevance in microbial immunity; and third, association of granulysin expression in natural killer cells with good outcomes in cancer, indicating its potential utility as a diagnostic and suggesting its relevance to human disease.
Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice
- D Kagi
- B Ledermann
- K Burki
- P Seiler
- B Odermatt
- K J Olsen
- E R Podack
- R M Zinkernagel
- H Hengartner