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Olive oil contains dozens of phenolic compounds, each with its own unique health benefits. An advantage of these compounds is high bioavailability. Many kinds of research highlight the anti-inflammatory, antimicrobial, antibacterial and antiviral properties of these compounds.

Infections and infectious diseases are due to viruses, bacteria, parasites, fungi, and various pathogens. When the human body contracts an infection, it relies on the immune system to fight it. Although there are drugs for the treatment of infections, some foods of natural origin, such as olive oil, also provide good results in the prevention and treatment of infections.

In olive oil, there are several polyphenols with antibacterial properties against human pathogens, specifically hydroxytyrosol, and oleuropein, which have also shown to have antiviral properties.

A study, published in National Center for Biotechnology Information in 2019, established that the consumption of extra virgin olive oil promotes good intestinal health.

The fatty acids contained in olive oil

Fatty acids, also known as food lipids, contained in olive oil are involved in the modulation of the immune system and inflammatory processes. Therefore, they offer important anti-inflammatory benefits to prevent and treat various health conditions.

https://ecobnb.com/blog/2020/05/stay-healthy-olive-oil-prevent-infection/

Background

Surgery is the mainstay therapy for HPV-induced laryngeal papillomatosis (LP) and adjuvant therapies are palliative at best. Research revealed that conjugated-linoleic acid (CLA) may improve the outcome of virally-induced diseases. The effects of Clarinol™ G-80 (CLA) and high oleic safflower oil (HOSF) on children with LP (concomitant with surgery) were evaluated.

Design

A randomized, double-blinded, crossover and reference-oil controlled trial was conducted at a South African medical university. Study components included clinical, HPV type/load and lymphocyte/cytokine analyses, according to routine laboratory methods.

Participants

Overall: ten children enrolled; eight completed the trial; five remained randomized; seven received CLA first; all treatments remained double-blinded.

Intervention

Children (4 to 12 years) received 2.5 ml p/d CLA (8 weeks) and 2.5 ml p/d HOSF (8 weeks) with a washout period (6 weeks) in-between. The one-year trial included a post-treatment period (30 weeks) and afterwards was a one-year follow-up period.

Main outcome measures

Changes in numbers of surgical procedures for improved disease outcome, total/anatomical scores (staging system) for papillomatosis prevention/viral inhibition, and lymphocyte/cytokine counts for immune responses between baselines and each treatment/end of trial were measured.

Findings

After each treatment all the children were in remission (no surgical procedures); after the trial two had recurrence (surgical procedures in post-treatment period); after the follow-up period three had recurrence (several surgical procedures) and five recovered (four had no surgical procedures). Effects of CLA (and HOSF to a lesser extent) were restricted to mildly/moderately aggressive papillomatosis. Children with low total scores (seven/less) and reduced infections (three/less laryngeal sub-sites) recovered after the trial. No harmful effects were observed. The number of surgical procedures during the trial (n6/available records) was significantly lower [(p 0.03) (95% CI 1.1; 0)]. Changes in scores between baselines and CLA treatments (n8) were significantly lower: total scores [(p 0.02) (95% CI −30.00; 0.00)]; anatomical scores [(p 0.008) (95% CI −33.00: -2.00)]. Immune enhancement could not be demonstrated.

Conclusions

These preliminary case and group findings pave the way for further research on the therapeutic potential of adjuvant CLA in the treatment of HPV-induced LP.

https://lipidworld.biomedcentral.com/articles/10.1186/1476-511X-11-136

Treatment of SARS-CoV-2 infection with a new antiviral drug, MK-4482/EIDD-2801 or Molnupiravir, completely suppresses virus transmission within 24 hours, researchers in the Institute for Biomedical Sciences at Georgia State University have discovered.

The group led by Dr. Richard Plemper, Distinguished University Professor at Georgia State, originally discovered that the drug is potent against influenza viruses.

"This is the first demonstration of an orally available drug to rapidly block SARS-CoV-2 transmission," said Plemper. "MK-4482/EIDD-2801 could be game-changing."

Interrupting widespread community transmission of SARS-CoV-2 until mass vaccination is available is paramount to managing COVID-19 and mitigating the catastrophic consequences of the pandemic.

Because the drug can be taken by mouth, treatment can be started early for a potentially three-fold benefit: inhibit patients' progress to severe disease, shorten the infectious phase to ease the emotional and socioeconomic toll of prolonged patient isolation and rapidly silence local outbreaks.

"We noted early on that MK-4482/EIDD-2801 has broad-spectrum activity against respiratory RNA viruses and that treating infected animals by mouth with the drug lowers the amount of shed viral particles by several orders of magnitude, dramatically reducing transmission," said Plemper. "These properties made MK-4482/EIDD/2801 a powerful candidate for pharmacologic control of COVID-19."

In the study published in Nature Microbiology, Plemper's team repurposed MK-4482/EIDD-2801 against SARS-CoV-2 and used a ferret model to test the effect of the drug on halting virus spread.

"We believe ferrets are a relevant transmission model because they readily spread SARS-CoV-2, but mostly do not develop severe disease, which closely resembles SARS-CoV-2 spread in young adults," said Dr. Robert Cox, a postdoctoral fellow in the Plemper group and a co-lead author of the study.

The researchers infected ferrets with SARS-CoV-2 and initiated treatment with MK-4482/EIDD-2801 when the animals started to shed virus from the nose.

"When we co-housed those infected and then treated source animals with untreated contact ferrets in the same cage, none of the contacts became infected," said Josef Wolf, a doctoral student in the Plemper lab and co-lead author of the study. By comparison, all contacts of source ferrets that had received placebo became infected.

If these ferret-based data translate to humans, COVID-19 patients treated with the drug could become non-infectious within 24 hours after the beginning of treatment.

MK-4482/EIDD-2801 is in advanced phase II/III clinical trials against SARS-CoV-2 infection.

Co-authors of the study include R.M. Cox, J.D. Wolf and R.K. Plemper at Georgia State.

The study was funded by public health service grants from the National Institutes of Health/National Institute of Allergy and Infectious Diseases to Georgia State

Indexed for Science Daily & NIH by Dragonfly Kingdom Library

https://www.sciencedaily.com/releases/2020/12/201203133908.htm

Natural triterpenes modulate immune-inflammatory markers of experimental autoimmune encephalomyelitis: therapeutic implications for multiple sclerosis

R Martín,* M Hernández, C Córdova, and ML Nieto

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Abstract

BACKGROUND AND PURPOSE

Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are inflammatory demyelinating diseases that develop as a result of deregulated immune responses causing glial activation and destruction of CNS tissues. Oleanolic acid and erythrodiol are natural triterpenes that display strong anti-inflammatory and immunomodulatory activities. Oleanolic acid beneficially influences the course of established EAE. We now extend our previous observations to erythrodiol and address the efficacy of both compounds to protect against EAE, given under different regimens.

EXPERIMENTAL APPROACH

The utility of both triterpenes in disease prevention was evaluated at a clinical and molecular level: in vivo through their prophylactic administration to myelin oligodendrocyte protein-immunized C57BL/6 mice, and in vitro through their addition to stimulated-BV2 microglial cells.

KEY RESULTS

These triterpenes protected against EAE by restricting infiltration of inflammatory cells into the CNS and by preventing blood–brain barrier disruption. Triterpene-pretreated EAE-mice exhibited less leptin secretion, and switched cytokine production towards a Th2/regulatory profile, with lower levels of Th1 and Th17 cytokines and higher expression of Th2 cytokines in both serum and spinal cord. Triterpenes also affected the humoral response causing auto-antibody production inhibition. In vitro, triterpenes inhibited ERK and rS6 phosphorylation and reduced the proliferative response, phagocytic properties and synthesis of proinflammatory mediators induced by the addition of inflammatory stimuli to microglia.

CONCLUSIONS AND IMPLICATIONS

Both triterpenes restricted the development of the characteristic features of EAE. We envision these natural products as novel helpful tools for intervention in autoimmune and neurodegenerative diseases including MS.

Keywords: encephalomyelitis, neuroimmunology, inflammation, microglia, pharmacology, triterpenes

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Introduction

Multiple sclerosis (MS) is an autoimmune demyelinating disease directed against myelin proteins of the brain and spinal cord, and is considered as one of the major neurological diseases in young adults (Noseworthy et al., 2000). The precise cause of MS is unknown, but one theory is that it might be triggered by exposure to a viral infection or environmental influences. The disease takes dissimilar courses in different people and can go into four main pathological subtypes, even leading to death in the very progressive form (Lassmann et al., 2001).

Experimental autoimmune encephalomyelitis (EAE) induced in susceptible strains of animals provides the best available model for understanding events in MS and to test new drugs that could lead to novel therapies (Steinman, 1999). MS/EAE pathogenesis is driven mostly by a Th1-mediated autoimmune response. The development of the disease includes breakdown of the blood–brain barrier (BBB), infiltration of the CNS – brain and spinal cord – by myelin-reactive T cells and macrophages, activation of resident CNS cells (microglia and astrocytes), demyelination and axonal loss (Merrill and Benveniste, 1996; Benveniste, 1997; Engelhardt, 2006).

Microglial cells are active participants throughout the MS disease process. ‘Activated’ microglia produces inflammatory cytokines, free radicals and attracts immune cells into the CNS. A diffuse activation of microglia throughout the brain serves as a source of inflammation inside the CNS in chronic MS/EAE, while at latter stages of the disease a chronically activated microglia is associated with impaired neural function (Rasmussen et al., 2007).

Other components of the immune system that play crucial roles in MS/EAE pathogenesis include dendritic and B cells, antibodies, as well as inflammation-related enzymes, cytokines and chemokines. Thus, COX-2 and inducible nitric oxide synthase (iNOS) enzymes and pro-inflammatory cytokines such as IFN-γ, TNF-α or IL-17 are considered to be pathogenic, while the Th2 cell-related cytokines IL-4 and IL-10 have been shown to down-regulate the immune response in acute EAE (Hafler, 2004; Imitola et al., 2005; Sospedra and Martin, 2005). Much progress has been made over the past decade in elucidating the causes and molecular basis of MS, but in spite of the extensive research performed to develop new pharmacotherapeutic approaches to slow down the disease progression, there are still no optimal therapies available, due to both unwanted side effects of the drugs and the clinical and immunopathological heterogeneity of this disease (Hemmer et al., 2006).

Oleanolic acid and erythrodiol are two natural triterpenes of the oleanane group present in many vegetables, including the leaves and fruits of Olea europea (the olive tree). They have been recognized to have hepatoprotective, anti-inflammatory and antihyperlipidemic properties. Indeed, oleanolic acid has been promoted in China as an oral drug for human liver disorders. Data correlated well with the traditional use of O. europea in African and European Mediterranean countries, where this plant has been utilized widely in folk medicine as a diuretic, hypotensive, hypoglycaemic, emollient, febrifuge and tonic, for urinary and bladder infections, for headaches, as well as a therapy for inflammatory pain (Dold and Cocks, 1999). Recently, a number of synthetic oleanane triterpenoid derivatives have been synthesized based on oleanolic acid with more potent activities, some of which are currently being developed for the treatment of chronic kidney diseases (Pergola et al., 2011) or as an attractive new therapeutic option for cancer patients by enhancing the effect of immunotherapy (Nagaraj et al., 2010). In the last years, a variety of novel pharmacological properties of triterpenoids have been reported: (i) beneficial effects on cardiovascular system due to antioxidant and vasorelaxant activities (Rodriguez-Rodriguez et al., 2006); (ii) interaction with cytochrome P450s; (iii) anti-proliferative activities on tumoural cells by activating apoptotic programmes (Martín et al., 2007; 2009); (iv) effects on intracellular redox balance and protective effects against lipid peroxidation; as well as (v) immunomodulatory effects (Marquez-Martin et al., 2006). Besides, we have shown that oleanolic acid has a therapeutic effect on an experimental model of MS (Martín et al., 2010), demonstrating that i.p. administration of oleanolic acid, in mice with established EAE, is capable of reducing important biomarkers related to EAE disease. However, the potential of these biologically active molecules on maintenance of health has not been addressed in depth, although disease prevention is a major goal on public health, particularly because of the shifting of the concept from ‘disease care’ to ‘health care’. Therefore, it has been of interest in the present study to assess the influence of early administration of oleanolic acid and erythrodiol, an intermediate from which oleanolic acid is formed and on which no previous data exist, on health promotion in our EAE model. Our findings confirmed that both erythrodiol and oleanolic acid markedly slowed the clinical manifestations of the disease and we were able to correlate the magnitude of improvement for EAE with the decrease of the immuno-inflammatory responses.

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Methods

Disease induction and treatment

All animal care and experimental protocols were reviewed and approved by the Animal Ethics Committee of the University of Valladolid and complied with the European Communities directive 86/609/ECC and Spanish legislation (BOE 252/34367-91, 2005) regulating animal research. C57BL/J6 mice (from Charles River Laboratories, Barcelona, Spain) were housed in the animal care facility at the Medical School of the University of Valladolid and provided food and water ad libitum.

Immunization

EAE was induced in 8 to 10-week-old female C57BL/J6 mice by subcutaneous immunization with 100 µg of myelin oligodendrocyte glycoprotein (MOG)35–55 peptide (MEVGWYRSPFSRVVHLYRNGK; from Dr F. Barahona, CBM, Madrid) emulsified in complete Freund's adjuvant containing 0.4 mg Mycobacterium tuberculosis (H37Ra; Difco, Detroit, MI, USA) on day 0. Additionally, mice received 300 ng of Pertussis toxin i.p. on days 0 and 2. Clinical signs of EAE were assessed daily in a double-blind manner on a scale of 0 to 5, with 0.5 points for intermediate clinical findings: grade 0, no abnormality; grade 0.5, partial loss/reduced tail tone, assessed by inability to curl the distal end of the tail; grade 1, tail atony; grade 1,5, slightly/moderately clumsy gait, impaired righting ability or combination; grade 2, hind limb weakness; grade 2,5, partial hind limb paralysis; grade 3, complete hind limb paralysis; grade 3,5, complete hind limb paralysis and fore limb weakness; grade 4, tetraplegic; grade 5, moribund state or death. Scores from two investigators, both unaware of the treatments, were averaged. Data were plotted as daily mean clinical score for all animals in a particular treatment group. Scores of asymptomatic mice (score = 0) were included in the calculation of the daily mean clinical score for each group. Mice scoring at level 4 for 2 days were automatically given a disease severity grade of 5 and killed.

Triterpene treatment procedure

MOG-Immunized mice were treated daily with 50 mg kg–1 day–1 of oleanolic acid or erythrodiol by i.p. injection beginning at different times.

Groups OA0 and ERY0: triterpene treatment started at the immunization day.

Groups OA-7 and ERY-7: triterpene treatment started on day -7, before EAE induction.

Groups OA12 and ERY12: triterpene treatment started on day 12 after EAE induction.

Control groups (without EAE induction):

Group control, C: treated daily with 0.2% w/v DMSO.

Groups OA and ERY: healthy mice treated with the triterpenes for the same time as the corresponding EAE mice.

Animals were studied at two different times:

30 days after immunization, when EAE mice showed hind limb paralysis, or

at the day when severe symptoms (score 5) in each animal group were apparent. This was at day 40 in untreated EAE mice and at day 110 for triterpene-treated EAE mice, after immunization.

Control mice (without EAE induction) were also injected daily with oleanolic acid or erythrodiol for an equivalent period of time.

Oleanolic acid and erythrodiol (Extrasynthese, Genay Cedex, France) were first dissolved in 2% w/v DMSO and then diluted with PBS for each experiment (the final concentration of DMSO was 0.2%, w/v).

Histological studies

Spinal cord tissue was obtained from five representative animals of the different experimental groups on day 30 after immunization. Tissues were fixed and embedded in paraffin, cut on a microtome (5 µm thicknesses), stained with eosin-haematoxylin. Histological examination was performed with a Nikon Eclipse 90i (Nikon Instruments, Inc., Amstelveen, the Netherlands) connected to a DXM1200C digital camera (Nikon Instruments Inc). Sections from 4–10 segments per mouse were examined by one investigator, without knowledge of the treatments.

Intravital microscopy in mouse brain

Intravital microscopy of the mouse cerebromicrovasculature was performed as previously described (Martín et al., 2010). Briefly, mice were anaesthetized at day 30 post-immunization by i.p. injection of a mixture of 100 mg·kg−1 ketamine and 10 mg·kg−1 xylazine, and the tail vein was cannulated for administration of fluorescent dyes. A craniotomy was performed using a high-speed drill (Dremel, Madrid, Spain) and the dura matter was removed to expose the underlying pial vasculature. The mouse was maintained at 37°C throughout the experiment and the exposed brain was continuously superfused with artificial CSF buffer at 37°C.

Leukocytes were fluorescently labelled by i.v. administration of rhodamine 6G (5 mg·kg−1 body weight) and visualized by a Zeiss Axioplan 2 imaging microscope (Hertfordshire, UK) connected to an AxioCam MR digital camera using the AxioVision AC imaging software and an Acroplan 20x/0.50W Ph2 lens. Eight different post-capillary venules of diameter between 30 and 70 µm were chosen for observation. Rolling leukocytes were defined as white cells moving at a velocity less than that of erythrocytes. Leukocytes remaining stationary for 30 s or longer were considered adherent to the venular endothelium. Leukocyte adhesion was expressed as cells/mm2 of venular surface area, as shown previously (Martín et al., 2010).

Evaluation of cytokines and MOG-specific antibodies by elisa

Anti-MOG-specific IgM and IgG isotypes were detected in serum samples collected from animals on day 30 after immunization, using elisa. In brief, 96-well polystyrene microtitre plates were coated with 0.5 mg per well of MOG35–55 peptide diluted in PBS overnight in a humidified chamber followed by PBS washing and blocking for 1 h with 5% BSA in PBS. Wells were incubated in duplicate with serum samples diluted 1:60 in PBS for 2 h at room temperature. After washing, HRP-labelled rat anti-mouse IgM, anti-mouse IgG, anti-mouse IgG1 and anti-mouse IgG2a (1:2000) from Serotec (Sigma-Aldrich, St Louis, MO, USA) were subsequently added for 90 min. After another washing, adding the substrate, and arresting the reaction with 0.1N HCl, absorbance was read at 450 nm. Data are expressed as mean optical density at 450 nm.

Leptin levels in serum samples and spinal cord tissue were determined by elisa (RayBiotech, Norcross, GA, USA). For cytokine quantification (IL-4, IL-6, IL-10, IL-17, TNF-α, and IFN-γ), cell culture medium, serum and spinal cord tissue were analysed by elisa according to the manufacturer's protocols (eBioscience, San Diego, CA, USA). Spinal cords were removed on day 30 after immunization or at the severe stage of the disease (score 5), weighed and then frozen at −80°C. SC tissue was homogenized by using a tissue homogenizer (Cole-Parmer Instrument, Vernon Hills, IL, USA) in an ice bath in 0.5 mL ice-cold PBS supplemented with 0.4 M NaCl, 0.05% Tween 20, 0.5% BSA and a protease inhibitor cocktail: 20 µg·mL−1 of leupeptin, 20 KI units of aprotinin, 0.1 mM phenylmethylsulphonyl fluoride (Sigma-Aldrich), and centrifuged at 3000× g for 10 min at 4°C. Supernatant were stored at −80°C until cytokine assays were performed. Total protein was assayed using the Bradford method. A 50 to 100 µL sample of each supernatant was used for tests.

Data were processed and expressed as pg of cytokine per mg of spinal cord wet weight, or pg of cytokine per mL for serum samples.

BBB permeability measurement

To evaluate BBB disruption, we measured the extravasation of Evans blue (EB) dye as a marker of albumin extravasation. At 30–31 days following EAE induction, mice were injected i.p. with 1 mL of 4% w/v EB. After 4 h, mice were killed, perfused, and brain and spinal cords were removed. Dye was extracted for 2–3 days in formamide (4 mL·g−1 of wet tissue) at room temperature. Extracted dye concentration was determined by measuring the absorbance at 650 nm. CNS tissue was dried 24 h at 60°C and weighed. Calculations were based on external standard readings and extravasated dye was expressed as mg of EB per mg dried weight of tissue.

Cell culture

Murine BV-2 cells, an immortalized murine microglia cell line, exhibit phenotypic and functional properties comparable with those of primary microglia and hippocampal neurons (Bocchini et al., 1992). BV-2 cells (a gift from Prof J. Bethea, Miller School of Medicine, Miami, FL, USA) were cultured in Dulbecco's modified Eagle's medium high sucrose, supplemented with 10% fetal bovine serum (FBS), 100 U·mL−1 penicillin and 100 µg·mL−1 streptomycin, and kept at 37°C in 5% CO2. Cells were seeded in 96-well plates (5 × 104 cells per well) or 60 mm culture dishes (3 × 106 cells per well.).

Proliferation assay

Cell proliferation was quantified by using the Promega kit (Madison, WI, USA), Cell Titer 96® Aqueous One Solution Cell Proliferation Assay, according to the manufacturer's recommendations. Briefly, cells were seeded in 96-well plates and serum starved for 24 h. Then, cells were treated in triplicate with IFN-γ, leptin or LPS, in the presence or absence of the triterpenes. After 24 h of incubation, formazan product formation was assayed by recording the absorbance at 490 nm in a 96-well plate reader (OD value). Formazan is measured as an assessment of the number of metabolically active cells and expressed in percentages relative to FBS-stimulated cells. Cell viability was assessed by Trypan blue exclusion.

Western blot analysis

Cells were washed with PBS and harvested in Laemmli SDS sample buffer. Protein extracts were separated by SDS-PAGE and transferred to polyvinylidene difluoride membranes. Membranes were blocked with 5% BSA-TBST at room temperature and then incubated for 18 h at 4°C with the indicated antibodies including ERK 1/2 (Zymed Laboratories, South San Francisco, CA, USA), rabbit p-ERK1/2, p-rS6 (Cell Signaling Technology, Danvers, MA, USA), COX-2 (sc-1745, Santa Cruz Biotech, Santa Cruz, CA, USA), actin (sc-8432, Santa Cruz Biotech) and iNOS (BD Biosciences, Lexington, KY, USA). After washing with TBST buffer, a 1:2.000 (v/v) dilution of horseradish peroxidase-labelled IgG was added at room temperature for 1 h. The blots were developed using enhanced chemiluminescence.

Phagocytosis assays

Cells were stimulated in serum-free media with or without 100 UI·mL−1 of IFN-γ, 1 µg·mL−1 of LPS or 0.5 µM of leptin for 24 h, in the presence or absence of different doses of oleanolic acid or erythrodiol and then exposed to 0.1 mg·mL−1 of FITC-labelled dextran (MW 40 000) for 2 h. Non-internalized particles were removed by vigorous washing with cold PBS (pH 7.4) prior to measuring fluorescence at 480 nm excitation and 520 nm emission on either a Flow Cytometer (Gallios™; Beckman Coulter, Fullerton, CA, USA) or a Fluoroskan multiwell plate reader (TECAN Genios Pro; Tecan Group Ltd, Zurich, Switzerland). Cultures without fluospheres were used (blank wells) as background. Each culture condition was done in triplicate, and three independent experiments were performed. To confirm that the fluospheres were accumulated intracellularly, a Leica TCS SP5X confocal microscope was used with the Leica LAS AF acquisition software (Wetzlar, Germany) and a ×60 oil objective.

Statistical analyses

Statistical analysis was performed with the GraphPad Prism Version 4 software (San Diego, CA, USA) by anova. Analyses were performed using repeated measures anova (or two-way anova) for comparison of clinical parameters, and one-way anova for comparison of parameters such as cytokines, extravasation, leukocytes and MOG antibodies. A post hoc analysis was made by the Bonferroni's multiple comparison test. P < 0.05 was considered statistically significant.

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Results

Effects of preventive treatment with oleanolic acid or erythrodiol on clinical EAE

Female C57BL/6 mice exhibit active EAE after immunization with the MOG35–55 peptide. In this experimental model we compared the effects of two pentacyclic triterpenes, oleanolic acid and erythrodiol given at a dose (50 mg·kg−1) previously proven to be both safe and therapeutically relevant in rodents (Jeong, 1999; Senthil et al., 2007; Martín et al., 2010) in two regimens: 7 days before immunization (day -7; OA-7, ERY-7) or at the day of induction (day 0; OA0, ERY0). The clinical analysis of the different groups of animals is shown in Figure 1. The placebo-treated animals developed neurological symptoms of active EAE after 12 to 31 days, consisting of tail limpness and a mild-to-moderate paraparesis, as well as progressive weight loss. Interestingly, when oleanolic acid or erythrodiol were administered from the day of induction, clinical disease was markedly less severe and mice had a later onset of the clinical signs compared with untreated animals with EAE (Figure 1A). First neurological symptoms (score 1) were observed at day 11 with mean day of onset 13.5 ± 2 in untreated EAE mice, while OA0 or ERY0 animals showed no clinical signs at that time and a similar score (tail atony) was first reached on day 27 (mean values 33 ± 2 and 34 ± 2 days respectively). When the triterpenes were given as a pre-treatment, starting 1 week before EAE induction, clinical disease remained mostly suppressed for the duration of the experiment (until day 30 post-induction)........... https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3419913/

Natural small molecules as inhibitors of coronavirus lipid-dependent attachment to host cells: a possible strategy for reducing SARS-COV-2 infectivity?

Mirko Baglivo 1, Manuela Baronio 2, Giuseppe Natalini 3, Tommaso Beccari 4, Pietro Chiurazzi 5, Ezio Fulcheri 6, Paolo Pietro Petralia 7, Sandro Michelini 8, Giovanni Fiorentini 9, Giacinto Abele Miggiano 10, Assunta Morresi 11, Gerolamo Tonini 12, Matteo Bertelli 13

Affiliations expand

PMID: 32191676 PMCID: PMC7569585 DOI: 10.23750/abm.v91i1.9402

Free PMC article

Abstract

Background: Viral infectivity depends on interactions between components of the host cell plasma membrane and the virus envelope. Here we review strategies that could help stem the advance of the SARS-COV-2 epidemic.

Methods and results: We focus on the role of lipid structures, such as lipid rafts and cholesterol, involved in the process, mediated by endocytosis, by which viruses attach to and infect cells. Previous studies have shown that many naturally derived substances, such as cyclodextrin and sterols, could reduce the infectivity of many types of viruses, including the coronavirus family, through interference with lipid-dependent attachment to human host cells.

Conclusions: Certain molecules prove able to reduce the infectivity of some coronaviruses, possibly by inhibiting viral lipid-dependent attachment to host cells. More research into these molecules and methods would be worthwhile as it could provide insights the mechanism of transmission of SARS-COV-2 and, into how they could become a basis for new antiviral strategies.   https://pubmed.ncbi.nlm.nih.gov/32191676/

Diet and Immune Function

Caroline E. Childs,1 Philip C. Calder,1,2 and Elizabeth A. Miles1,*

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Abstract

A well-functioning immune system is critical for survival. The immune system must be constantly alert, monitoring for signs of invasion or danger. Cells of the immune system must be able to distinguish self from non-self and furthermore discriminate between non-self molecules which are harmful (e.g., those from pathogens) and innocuous non-self molecules (e.g., from food). This Special Issue of Nutrients explores the relationship between diet and nutrients and immune function. In this preface, we outline the key functions of the immune system, and how it interacts with nutrients across the life course, highlighting the work included within this Special Issue. This includes the role of macronutrients, micronutrients, and the gut microbiome in mediating immunological effects. Nutritional modulation of the immune system has applications within the clinical setting, but can also have a role in healthy populations, acting to reduce or delay the onset of immune-mediated chronic diseases. Ongoing research in this field will ultimately lead to a better understanding of the role of diet and nutrients in immune function and will facilitate the use of bespoke nutrition to improve human health.

Keywords: nutrition, immunity, macronutrients, micronutrients, microbiome, life course, probiotic, prebiotic, inflammation

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1. Overview of the Immune System

Broadly, cells of the immune system may be divided into those of the innate and those of the adaptive immune response. The innate response is the first response to an invading pathogen. Cells of the innate immune response include phagocytes (e.g., macrophages and monocytes), neutrophils, dendritic cells, mast cells, eosinophils, and others. The innate response is rapid, but not specialised and is generally less effective than the adaptive immune response.

The adaptive immune response has the ability to specifically recognise a pathogen and ‘remember’ it if exposed to it again. T cells are critical in antigen recognition and the co-ordination of the immune response. T cells are present in an array of subtypes that coordinate different types of immune responses. Broadly, they are divided into the cytotoxic T cells (bearing the CD8 receptor), which are involved in direct killing of infected damaged cells and tumour cells, and the T helper cells. T helper (Th) cells bear the CD4 receptor and are important in coordinating the responses of other immune cells. There are a number of subtypes of Th cells, defined by the cytokines they produce. Initial studies identified two subsets, the Th1 cells, which produced interferon gamma (IFN-γ) and interleukin (IL)-2 and were important in antiviral and cellular immune responses, and the Th2 subset producing IL-4, IL-5, and IL-13 and involved in humoral (antibody) and anti-parasitic responses (but also in allergic responses) [1]. It is now apparent that there are a number of other Th subtypes, which do not fall into these categories. This includes Th17 cells, which produce IL-17A, IL-17F, and IL-22 and are important in fighting extracellular pathogens (bacteria and fungi) [2]. There are also T regulatory cells (Treg), which are CD4-bearing T cells vital in maintaining immune tolerance to allow the immune system to ignore non-harmful non-self (such as food, pollen, and environmental antigens such as latex). Thus, the role of T cells is coordinating an appropriate immune response following immune stimulation or challenge.

The other lymphocytes of the adaptive immune system are the B cells, which are responsible for antibody or immunoglobulin (Ig) production. Like T cells, B cells respond specifically to an antigen. They can differentiate into short-lived plasma cells, which produce Igs in the short term, or can become long-lived plasma cells. Igs are pathogen-specific molecules, which help the immune system to recognise and destroy pathogens. The B cells can differentiate into plasma cells, which produce one of five classes of Ig (IgM, IgD, IgG, IgA, and IgE). Each class of Ig has a specialised role [3]. IgM is the first Ig expressed during development, is often found as a multimeric molecule (e.g., pentameric), and can bind an antigen to identify it for destruction by immune cells. IgD is found in low concentrations in the plasma and the specialist role of IgD is not yet clear. IgG is the predominant Ig class and can persist for long periods. It has important roles in antigen labelling, resulting in more effective removal. IgA can be found in the serum (mostly as a monomer) and at mucosal surfaces (normally as a dimer). At the mucosal surface, IgA protects against bacteria and or viruses, preventing infection. IgA also has an important role in neutralising food antigens and helping to maintain immune tolerance to food antigens (preventing the development of food allergy) [4]. IgE has a role in clearance of extracellular parasites (e.g., helminths) but when produced inappropriately to innocuous environmental and food antigens, has an important role in IgE-mediated allergy. B cells go through a process called class switching to set the class of Ig that the plasma cells derived from them will produce. B cell class switching is controlled by the cytokines present, particularly IL-4, IL-6, and IFN-γ secreted from Th cells [5].

T and B cells can specialise to become memory cells, which persist permanently or for very long periods and are able to recognise the antigen if encountered again and elicit a rapid, pathogen-specific immune response.

The effective deployment of the immune system against pathogens or harmful signals and the swift resolution of the immune response is required for survival. The fighting of infection is only one piece of the puzzle. A fulminating immune response is costly in terms of energy expended and results in damage to the host tissues; thus, rapid and complete resolution of an immune response is also key. Cytokines play a role in resolution of immune responses. IL-10, which is produced by a range of immune cells including Tregs, has anti-inflammatory actions including suppressing inflammatory cytokine production [6].

The instigation of an immune response and the activities of the immune cells results in inflammation (seen as redness, swelling, and the feeling of heat and pain), which are signs of the damage to the tissue going on whilst the immune system does its work. This is an expected outcome of an effective immune response. Increasingly there is concern that modern lifestyle changes have resulted in the promotion of ongoing, low-grade, whole-body (systemic) inflammation caused by immune and other cells (e.g., adipocytes, the cells that store lipids in fat tissue) [7]. Such exposures may include diet quality and quantity [8].

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2. The Role of Nutrition in Immune Function

Adequate and appropriate nutrition is required for all cells to function optimally and this includes the cells in the immune system. An “activated” immune system further increases the demand for energy during periods of infection, with greater basal energy expenditure during fever for example. Thus, optimal nutrition for the best immunological outcomes would be nutrition, which supports the functions of immune cells allowing them to initiate effective responses against pathogens but also to resolve the response rapidly when necessary and to avoid any underlying chronic inflammation. The immune system’s demands for energy and nutrients can be met from exogenous sources i.e., the diet, or if dietary sources are inadequate, from endogenous sources such as body stores. Some micronutrients and dietary components have very specific roles in the development and maintenance of an effective immune system throughout the life course or in reducing chronic inflammation. For example, the amino acid arginine is essential for the generation of nitric oxide by macrophages, and the micronutrients vitamin A and zinc regulate cell division and so are essential for a successful proliferative response within the immune system.

Undernutrition is well understood to impair immune function, whether as a result of food shortages or famines in developing countries, or as a result of malnutrition arising from periods of hospitalisation in developed countries. The extent of impairment that results will depend upon the severity of the deficiency, whether there are nutrient interactions to consider, the presence of infection, and the age of the subject [9]. A single nutrient can also exert multiple diverse immunological effects, such as in the case of vitamin E, where it has a role as both antioxidant, inhibitor of protein kinase C activity, and potentially interacting with enzymes and transport proteins [10]. For some micronutrients, excessive intake can also be associated with impaired immune responses. For example, supplementation with iron can increase morbidity and mortality of those in malaria endemic regions. As well as nutrition having the potential to effectively treat immune deficiencies related to poor intake, there is a great deal of research interest in whether specific nutrient interventions can further enhance immune function in sub-clinical situations, and so prevent the onset of infections or chronic inflammatory diseases.

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3. Gut-Associated Lymphoid Tissue

The majority of immune cells within the human body are found within the gut-associated lymphoid tissue (GALT), reflecting the importance of this immune tissue in maintaining host health. In ingesting food, we expose ourselves to near constant and massive antigenic stimulation, and our immune system must be able to provide strong and protective immunity against invasive pathogens, while tolerating food proteins and commensal bacteria. In order to achieve this, the GALT contains a variety of sensing and effector immune functions. Dendritic cells and M cells sample the gut content, while plasma B cells within the lamina propria produce IgA, providing protection against pathogenic organisms. Specialised immune regions known as Peyer’s patches, rich in immune cells, allow for communication between immune cells resident within the GALT, propagation of signals to the wider systemic immune system, and the recruitment or efflux of immune cells [11].

Within the gut lumen itself, the human gut microbiome will provide antigens and signals with the potential to interact with resident and systemic immune cells. The composition of the gut microbiome changes over the life course, in response to dietary components, and to environmental factors such as antibiotic exposure. Dietary interventions targeted at the gut microbiome include probiotics and prebiotics. Probiotics are defined as “live microorganisms, which, when consumed in adequate amounts, confer a health benefit of the host” [12] while prebiotics, “a substrate that is selectively utilized by host microorganisms conferring a health benefit” [13], tend to be non-digestible oligosaccharides such as fructo-oligosaccharides and galacto-oligosaccharides. Provision of plant-based diets may enhance the diversity of nutrients that reach the gut microbiome, with the indigestibility of plant cell walls enabling peptides and lipids, which may otherwise have been absorbed in the upper digestive tract to reach the microbiome [14]. There may be circumstances in which immune cells of the GALT come into direct contact with nutrients or gut microbiota, such as in the case of reduced epithelial integrity, or ‘leaky gut’ observed in both acute and chronic gut inflammation [15]. Such changes in gut permeability may be influenced by micronutrient status such as that of vitamin D [16].

A number of nutrients and dietary interventions have demonstrated the capacity to improve measures of gut health or to reduce gut inflammation. Protein hydrolysates have been demonstrated to enhance barrier function and IgA production in animal models, and as a result may have applications for incorporation within hypo-allergenic infant formula and clinical nutrition for those with conditions such as inflammatory bowel disease [17]. Animal models of gut inflammation have identified that providing probiotic bacteria can reduce inflammation, with reductions in proinflammatory Th1 and Th17 cytokines such as IL-17 and IFN-γ, and enhanced production of inflammation resolving cytokine IL-10 [18]. Prebiotics can also enhance barrier function, in addition to their role as substrates for bacterial metabolism [19]. Santiago-Lopez et al. have investigated the effect of fermented milk on a murine model of inflammatory bowel disease [18] and demonstrated a reduction in serum IL-17 and IFN-γ following fermented milk consumption when compared with the control group.

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4. Immune Function Over the Life course

The developing foetus and neonates have an immature immune system, with poor antibody production and a low proliferative response to challenge. In utero, the foetus can gain passive protection from its mother via antibodies, which cross the placenta. This is the basis by which infants in the UK are provided with early protection against whooping cough, with mothers offered vaccination in their third trimester, in order to provide passive immunity to their infants until they reach the age of infant vaccinations. While immature, the foetal immune system can produce antibodies, and allergens can reach the developing foetus, and allergen-specific IgE can be detected in cord blood samples [20]. Another signature of the immaturity of the immune system in early life is the susceptibility of neonates to infections, and the associated higher burden of morbidity and mortality.

The development of the immune system in early life will be influenced by both feeding practices and environmental exposures. Breastfeeding provides further passive immunity to the infant, for example via transfer of antibodies and cytokines. Breast milk components can also stimulate maturation of the gut-associated lymphoid tissue, with breast milk known to be rich in bifidogenic oligosaccharides and to contain its own unique microbiota. Human milk oligosaccharides (HMOs) are synthesised from lactose in the mammary gland, and the specific HMO profile will vary between individuals and across contexts and changes over the time course of lactation [21]. These HMOs have been found to confer health benefits to infants by inhibiting the adhesion of microorganisms to the intestinal mucosa, enhancing the production of short-chain fatty acids by bacteria within the microbiome, and inhibiting inflammation [22]. Other immune active components of breast milk are also likely to be involved in immune system maturation, with studies identifying that the growth factors epidermal growth factor, fibroblast growth factor 21, and transforming growth factor-β2 can change lymphocyte phenotypes in new-born rats when provided as supplements by oral gavage [23].

In infancy, diverse environmental factors will impact upon immune system development; identified factors include pet ownership, antibiotic use, and the timing of introduction of foods [24]. The opportunity for introduction of prebiotic oligosaccharides during the introduction of foods has been explored, with the suggestion that this could provide a unique opportunity to influence the developing microbiome and thereby interact with the developing immune system [19]. These early years of life are a critical period in the development of the immune system, particularly for T cell function, with the thymus maturing and reaching its maximum size relative to body weight in infancy [25].

As we move through the life course towards later life, a decline in immune function is observed among older adults. As was the case in infancy, older adults are more susceptible to infections, and have more serious complications as a result than younger people. This declining immune function is known as immunosenescence and reflects deterioration of both the acquired and innate immune systems [26]. Declining T cell function with age arises from thymic involution and decreased thymic output, resulting in fewer naive T cells and more memory cells in the circulation [27]. Ageing is also associated with increased inflammation in the absence of infection and has been found to predict hospitalisation and death [28]. A number of micronutrient deficiencies have been identified as contributors to such declining immunity, and so may provide opportunities for targeted interventions to restore immune function [29].

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5. Chronic Systemic Inflammation

Chronic systemic inflammation is a key underlying feature for a range of chronic non-communicable disease conditions such as cardiovascular disease, stroke, and autoimmune disorders such as rheumatoid arthritis. This chronic inflammation is positively correlated with aging and other co-morbidities (e.g., obesity, cardiovascular disease, insulin resistance). Interestingly, in a study in healthy adults, increasing age was found to be a risk factor for chronic systemic inflammation, independent of other risk factors such as body mass index, blood pressure, and blood lipid profiles [30].

The rising worldwide prevalence of obesity in children and adults is of grave concern. Obesity and over nutrition are strongly associated with chronic inflammation, metabolic perturbation, and higher risk for a number of chronic diseases including cardiovascular disease, stroke, type 2 diabetes mellitus, and chronic liver disease. This metabolism-induced inflammation associated with obesity is termed metaflammation, and the Western diet is a known risk factor [31,32]. The Western diet is characterised by a diet high in sugar, trans and saturated fats, but low in complex carbohydrates, fibre, micronutrients, and other bioactive molecules such as polyphenols and omega 3 polyunsaturated fatty acids. The mechanisms by which the Western diet predispose individuals to metaflammation are still under investigation. However, one mechanism which has been reported is the increased uptake of lipopolysaccharide (LPS, a constituent of gram-negative bacterial cells walls), from microbes in the gut because of increased gut leakiness. This LPS is sensed by cells of the innate immune system through toll-like receptor 4 (TLR4). Activation of TLR4 by LPS will induce an inflammatory response by the immune cells. Certain nutrients, notably long-chain omega 3 polyunsaturated fatty acids, can interfere with TLR4 activation and, thus, can ameliorate this inflammatory signal. Rogero et al. describe the relationship between obesity and inflammation and explores the immune pathway for this mechanism and the anti-inflammatory roles of omega 3 fatty acids in this process [33].

Interestingly, in juxtaposition with the review by Rogero et al. on inflammation in obesity, Dalton and colleagues report a study into systemic inflammation in individuals with the serious psychological eating disorder, anorexia nervosa [34]. They show that in a severely undernourished state, there are indications of systemic inflammation with an increased serum concentration of IL-6 when compared with healthy control participants. IL-6 is a classically inflammatory cytokine produced by immune and other cells. Whether this inflammation is the result of the impact of undernutrition or whether the clinical condition is the result of pre-existing inflammation is a matter that remains to be determined. It has been shown that patients with clinical depression have increased systemic inflammation suggesting that inflammation may have a bearing on mental health and wellbeing [35].

In contrast with the Western diet, the Mediterranean diet is rich in vegetables, fruit, nuts, legumes, fish, and ‘healthy’ dietary fats. The Mediterranean diet is associated with a reduced risk of chronic disease such as cardiovascular disease, cancer, and more recently Alzheimer’s disease [36]. A range of bioactive compounds found in fruits and vegetables have been reported to offer one explanation for the protective effect of diets rich in fruits and vegetables (e.g., Mediterranean diet) on the reduction of risk for developing non-communicable diseases attributed to chronic inflammation (e.g., cardiovascular disease). One family of molecules, which are known to have a role in regulation of inflammation are the dietary polyphenols [37]. Yahfoufi et al. explain the mechanisms by which polyphenols can be immunomodulatory and anti-inflammatory and explore the evidence for the role of dietary polyphenols in reducing the risk of cardiovascular disease, some neurological diseases, and cancer [38].

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6. Nutrition in the Clinical Setting

In clinical settings, acute inflammation may be a sudden, severe, and overwhelming process. If not controlled, this severe systemic inflammation results in sepsis, culminating in multiple organ failure and death. Sepsis is a major global cause of death killing approximately 6 million people per year and is estimated to be the cause of 30% of neonatal deaths [39]. In this Special Issue of Nutrients, the role of zinc in sepsis is discussed [40]. Zinc is known to be an important micronutrient for the immune system. It has a role as a cofactor with both catalytic and structural roles in many proteins [41]. Even a mild deficiency in zinc has been associated with widespread defects in both the adaptive and innate immune response [42]. During sepsis, zinc homeostasis is profoundly altered with zinc moving from the serum into the liver. Alker and Haase consider this phenomenon and the implications for therapeutic options to improve outcomes in patients presenting with sepsis [40].

Selenium is a trace element that, like zinc, has critical functional, structural, and enzymatic roles, in a range of proteins. Poor selenium status is associated with a higher risk for range of chronic diseases including cancer and cardiovascular disease [43]. In addition to critical roles in many non-immune tissues within the body, selenium is important for optimal immune function. Avery and Hoffman explain the role of selenium in immunobiology and the mechanisms by which selenoproteins regulate immunity. The evidence for the significance of selenium status in infectious diseases including human immunodeficiency virus infection is reviewed [44].

Glutamine is a nonessential amino acid that provides an important energy source for many cell types including those involved in immune responses. It also serves as a precursor for nucleotide synthesis, particularly relevant for rapidly dividing cells such as the immune cells during an immune response. During infection, the rate of glutamine consumption by immune cells is equivalent or greater than that for glucose. Glutamine has roles in the functions of a number of immune cells including neutrophils, macrophages, and lymphocytes [45]. In catabolic conditions (e.g., infection, inflammation, trauma), glutamine is released into the circulation, an essential process controlled by metabolic organs such as the liver, gut, and skeletal muscles. Despite this adaptation, a significant depletion of glutamine is seen in the plasma and tissues in critical illness, which has provided a rationale for the use of in clinical nutrition supplementation of critically ill patients. How glutamine homeostasis is maintained and when and how to utilise glutamine in the clinical setting is explored in a review by Cruzat et al. [45].

The vitamin D receptor (VDR) is a nuclear receptor that can directly affect gene expression [46]. The presence of VDR in the majority of immune cells immediately suggests an important role for this micronutrient in immune cell activities [47]. Furthermore, vitamin D-activating enzyme 1-α-hydroxylase (CYP27B1), which results in the active metabolite 1 α,25-dihydroxyvitamin D3 (1,25(OH)2D3), is expressed in many types of immune cells. Ligation of VDR by 1,25(OH)2D3 can elicit the production of antimicrobial proteins and influence cytokine production by immune cells [47,48]. Sassi, Tamone, and d’Amelio have reviewed the evidence for the role of the nutrient vitamin D in the innate and adaptive immune systems [16].

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7. Conclusions

In this Special Issue of Nutrients, the collected works provide a breadth of reviews and research indicating the key influence of nutrients and nutrition on immune responses in health and disease and across the life course. Nutrients may impact directly or indirectly upon immune cells causing changes in their function or may exert effects via changes in the gut microbiome. A better understanding of the role of nutrients in immune function will facilitate the use of bespoke nutrition to improve human health.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723551/

Neighborhood Disparities in Access to Healthy Foods and Their Effects on Environmental Justice

Angela Hilmers, MD, MS,corresponding author David C. Hilmers, MD, MPH,corresponding author and Jayna Dave, PhD

Author information Article notes Copyright and License information Disclaimer

This article has been cited by other articles in PMC.

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Abstract

Environmental justice is concerned with an equitable distribution of environmental burdens. These burdens comprise immediate health hazards as well as subtle inequities, such as limited access to healthy foods.

We reviewed the literature on neighborhood disparities in access to fast-food outlets and convenience stores. Low-income neighborhoods offered greater access to food sources that promote unhealthy eating. The distribution of fast-food outlets and convenience stores differed by the racial/ethnic characteristics of the neighborhood.

Further research is needed to address the limitations of current studies, identify effective policy actions to achieve environmental justice, and evaluate intervention strategies to promote lifelong healthy eating habits, optimum health, and vibrant communities.

ENVIRONMENTAL JUSTICE HAS been defined as

fair treatment and meaningful involvement of all people regardless of race, ethnicity, income, national origin, or educational level in the development, implementation, and enforcement of environmental laws, regulations, and policies.1(p1)

Fair treatment signifies that “no population, due to policy or economic disempowerment, is forced to bear a disproportionate exposure to and burden of harmful environmental conditions.”1(p1) The concept of environmental justice, which has its roots in the fight against toxic landfills in economically distressed areas, can be similarly applied to the inequitable distribution of unhealthy food sources across socioeconomic and ethnic strata.1 The neighborhood environment can help promote and sustain beneficial lifestyle patterns or can contribute to the development of unhealthy behaviors, resulting in chronic health problems among residents.2–4 The higher prevalence of obesity among low-income and minority populations has been related to their limited access to healthy foods5–18 and to a higher density of fast-food outlets and convenience stores where they live.9,19–21 These environmental barriers to healthy living represent a significant challenge to ethnic minorities and underserved populations and violate the principle of fair treatment.

Several studies have investigated disparities in the distribution of neighborhood vegetation,22,23 the proximity of residences to playgrounds,24 and the accessibility of supermarkets and grocery stores,25,26 but fewer have examined access to fast-food outlets and convenience stores as a function of neighborhood racial and socioeconomic demographics. To our knowledge, our review is the first to expand the focus of environmental justice from environmental hazards and toxic exposures to issues of the food environment by examining research on socioeconomic, ethnic, and racial disparities in neighborhood access to fast-food outlets and convenience stores.

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METHODS

We reviewed studies of differences in accessibility of fast-food outlets and convenience stores by the socioeconomic and racial/ethnic characteristics of neighborhoods. With the assistance of an experienced health science librarian, we conducted searches in the MEDLINE, PubMed, PsycINFO, EBSCO Academic Search Premier, and Scopus databases. Key words were “neighborhood deprivation,” “food environment,” “food sources,” “fast-food restaurants,” “convenience stores,” “bodegas,” “disparity,” “inequality,” “minorities,” “racial/ethnic segregation,” and “socioeconomic segregation.” We included only original, peer-reviewed studies published in English between 2000 and 2011. Comments, editorials, dissertations, conference proceedings, newsletters, and policy statements were excluded. We also excluded studies that focused on methods and measurements, did not examine socioeconomic or racial/ethnic characteristics of the neighborhood, or used schools as a proxy for neighborhood environment.

Our search identified 501 unique citations; after detailed inspection, we selected 24. The primary reasons for exclusion were irrelevant outcomes or comparisons (n = 316), focus on dietary behavior (n = 96), and methodology studies (n = 65). We defined fast-food outlets as

take-away or take-out providers, often with a ‘drive-thru’ service which allows customers to order and pick up food from their cars; but most also have a seating area in which customers can eat the food on the premises (http://www.merriam-webster.com).

Examples of fast-food outlets were fast-food restaurant chains, take-away or carry-out establishments, and small local fast-food businesses. We defined convenience stores as

retail stores that sell a combination of gasoline, fast foods, soft drinks, dairy products, beer, cigarettes, publications, grocery items, snacks, and nonfood items and have a size less than 5000 square feet.27(p996) .......... https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3482049/

Indexed for National Institute Of Health by Dragonfly Kingdom Library

Speleotherapy for asthma

S Beamon 1, A Falkenbach, G Fainburg, K Linde

PMID: 11406004 DOI: 10.1002/14651858.CD001741

Abstract

Background: Speleotherapy, the use of subterranean environments, is a therapeutic measure in the treatment of chronic obstructive airways diseases. It is virtually unknown in the UK or the US, but has considerable widespread use in some Central and Eastern European countries.

Objectives: To review evidence for the efficacy of speleotherapy in the treatment of asthma.

Search strategy: We searched electronic databases (Medline, Embase, Cochrane Airways group database), contacted speleotherapy centres and experts in the field, hand searched proceedings, and checked bibliographies of articles obtained to identify possible relevant publications.

Selection criteria: We included controlled clinical trials (i.e., both randomized and those not reporting the method of allocation) that compared clinical effects of speleotherapy with another intervention or no intervention in patients with chronic asthma.

Data collection and analysis: Information concerning patients, interventions, results, and methodology were extracted in standardized manner by two independent reviewers and summarized descriptively.

Main results: Three trials including a total of 124 asthmatic children met the inclusion criteria, but only one trial had reasonable methodological quality. Two trials reported that speleotherapy had a beneficial short-term effect on lung function. Other outcomes could not be assessed in a reliable manner. A further search was conducted in July 2000. One further paper was excluded (see excluded studies)

Reviewer's conclusions: The available evidence does not permit a reliable conclusion as to whether speleo-therapeutic interventions are effective for the treatment of chronic asthma. Randomized controlled trials with long-term follow-up are necessary.

Update of

Speleotherapy for asthma.

Beamon S, Falkenbach A, Fainburg G, Linde K.

Cochrane Database Syst Rev. 2000;(2):CD001741. doi: 10.1002/14651858.CD001741.

PMID: 10796665 Updated. Review.

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Freidl J, Huber D, Braunschmid H, Romodow C, Pichler C, Weisböck-Erdheim R, Mayr M, Hartl A.

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Impact of non-drug therapies on asthma control: A systematic review of the literature.

Schuers M, Chapron A, Guihard H, Bouchez T, Darmon D.

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New agents that are effective against common pathogens are needed particularly for those resistant to conventional antimicrobial agents. Essential oils (EOs) are known for their antimicrobial activity. Using the broth microdilution method, we showed that (1) two unique blends of Cinnamomum zeylanicum, Daucus carota, Eucalyptus globulus and Rosmarinus officinalis EOs (AB1 and AB2; cinnamon EOs from two different suppliers) were active against the fourteen Gram‐positive and ‐negative bacteria strains tested, including some antibiotic‐resistant strains. Minimal inhibitory concentrations (MICs) ranged from 0.01% to 3% v/v with minimal bactericidal concentrations from <0.01% to 6.00% v/v; (2) a blend of Cinnamomum zeylanicum, Daucus carota, Syzygium aromaticum, Origanum vulgare EOs was antifungal to the six Candida strains tested, with MICs ranging from 0.01% to 0.05% v/v with minimal fungicidal concentrations from 0.02% to 0.05% v/v. Blend AB1 was also effective against H1N1 and HSV1 viruses. With this dual activity, against H1N1 and against S. aureus and S. pneumoniae notably, AB1 may be interesting to treat influenza and postinfluenza bacterial pneumonia infections. These blends could be very useful in clinical practice to combat common infections including those caused by microorganisms resistant to antimicrobial drugs.

1. Introduction

Antimicrobial resistance poses a serious threat to the effective treatment of an ever‐increasing range of infections caused by bacteria, fungi and viruses. Worldwide, antibiotic resistance is increasing. For example, Escherichia coli, Klebsiella pneumoniae, Streptococcus pneumoniae have reported reduced antibiotic susceptibility, which exceeded 50% in most countries that provided data to the WHO Antimicrobial Resistance Global Report on Surveillance (WHO, 2014). Candidiasis has also become substantially problematic, with Candida albicans showing increased resistance to common antifungal agents (Goncalves, Souza, Chowdhary, Meis, & Colombo, 2016; Hawser & Douglas, 1995). The recent pandemic of a novel H1N1 influenza viral strain and emerging strains resistant to commonly used anti‐herpes simplex drugs also emphasizes the need to identify effective approaches to prevent and treat viral infections (Boivin, 2013; James & Prichard, 2014).

This increasing resistance has created a need to develop new antimicrobial agents. Essential oils (EOs) are good candidates as studies have shown that individual EOs and their isolated compounds, including terpenes and terpenoids (1,8‐cineole, carvacrol) and aromatic compounds (cinnamaldehyde and eugenol) have antimicrobial activity against a wide range of pathogens, with various spectrums of activity (Bassole & Juliani, 2012; Friedman, Henika, & Mandrell, 2002; Jantan, Karim Moharam, Santhanam, & Jamal, 2008). The antimicrobial effects of EOs are linked to their composition and cytotoxic effects, which cause cell membrane damage. EO compounds are lipophilic, and so pass through the cell wall and cytoplasmic membrane. They disrupt the structure of the polysaccharide, fatty acid, and phospholipid layers, making the membrane permeable (Bakkali, Averbeck, Averbeck, & Idaomar, 2008). Unfortunately, EOs do not specifically target pathogens; they can also affect eukaryotic cells in a reversible or irreversible manner (Carson, Hammer, & Riley, 2006). In extreme cases, EO cytotoxicity can lead to apoptosis, necrosis, and organ failure (Tisserand & Young, 2013). Therefore, EOs have to be used carefully, within the daily intake limits defined by the relevant authorities when available (EMEA and HMPC 2010, 2011; FAO and WHO 2003).

Three different EO blends were formulated, taking into account the specific activity of each. The first two (AB1 and AB2) contained EOs from Cinnamomum zeylanicum, Daucus carota, Eucalyptus globulus, and Rosmarinus officinalis, which differed only in that the cinnamon EOs were provided by two different suppliers. These EOs were selected for their antibacterial effects that had been observed, either individually or in pairs, in previously published studies (for review see Bassole & Juliani, 2012). Eucalyptus globulus and Cinnamomum Zeylanicum EOs also have been reported to have antiviral activity (Astani, Reichling, & Schnitzler, 2010; Cermelli, Fabio, Fabio, & Quaglio, 2008; Vimalanathan & Hudson, 2014). The third blend (AF) contained EOs from Cinnamomum zeylanicum, Daucus carota, Syzygium aromaticum, Origanum vulgare, which are known for their antifungal activity (Khan & Ahmad, 2011; Pinto, Vale‐Silva, Cavaleiro, & Salgueiro, 2009; Tavares et al., 2008; Zore, Thakre, Jadhav, & Karuppayil, 2011).

The antibacterial activity of AB1 and AB2 was evaluated in vitro against a selection of Gram‐positive and Gram‐negative bacteria, with or without antibiotic resistance, AB1 was evaluated for antiviral activity and AF was assessed for activity against different Candida strains.

Inxed for NIH by Dragonfly Kingdom Library https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5552930/

Crystal Healing

Crystal healing is an alternative medicine technique that uses crystals and other stones as conduits for natural healing energy. Crystals vibrate at their own frequency, the same way that the cells in your body and your energetic centers vibrate at their own frequency. That means that when we come into contact with crystals these different frequencies meet and enhance your physical, emotional and spiritual balance. When placing a crystal on the body, the geometric and highly synchronized vibrations begin to merge with the bio-energetic field of the person and create a healing effect that can liberate and transform lower energy patterns.

While some dismiss this form of vibrational medicine, it is important to note that crystals are used in computers, radios, watches, fiber-optic technology, lasers and credit cards. The ability for crystals to store and transmit information is incredible. (https://upliftconnect.com/vibrational-medicine/)

Even the genius scientist Nikola Tesla said that crystals are actually living beings:

In a crystal we have clear evidence of the existence of a formative life principle, and though we cannot understand the life of a crystal, it is nonetheless a living being

Crystals and gemstones have been used for thousands of years as powerful healing aids. In addition to herbalism and acupuncture, Chinese Medicine has a rich tradition of using stones as medicine, passed from generation to generation for thousands of years, as do many other cultures. We may not always be conscious of it, but Crystal Therapy is part of our everyday life. Many people wear precious, semi-precious stones and different minerals not only as jewelry but for their healing benefits as well. Crystal healing is a powerful, yet gentle therapy that works on all levels of the body, mind and spirit. Crystals have the potential to help all of us in a specialized way. You’ll discover how they can draw in and radiate healing energy specific to each area of the body, mind, and spirit.

Indexed for Integrative Healing Arts Studio by Dragonfly Kingdom Library

COVID-19 and therapy with essential oils having antiviral, anti-inflammatory, and immunomodulatory properties

Muhammad Asif, Mohammad Saleem, Malik Saadullah, Hafiza Sidra Yaseen & Raghdaa Al Zarzour

Inflammopharmacology volume 28, pages1153–1161(2020)Cite this article

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Abstract

Coronavirus disease of 2019 (COVID-19) has emerged as a global health threat. Unfortunately, there are very limited approved drugs available with established efficacy against the SARs-CoV-2 virus and its inflammatory complications. Vaccine development is actively being researched, but it may take over a year to become available to general public. Certain medications, for example, dexamethasone, antimalarials (chloroquine/hydroxychloroquine), antiviral (remdesivir), and IL-6 receptor blocking monoclonal antibodies (tocilizumab), are used in various combinations as off-label medications to treat COVID-19. Essential oils (EOs) have long been known to have anti-inflammatory, immunomodulatory, bronchodilatory, and antiviral properties and are being proposed to have activity against SARC-CoV-2 virus. Owing to their lipophilic nature, EOs are advocated to penetrate viral membranes easily leading to membrane disruption. Moreover, EOs contain multiple active phytochemicals that can act synergistically on multiple stages of viral replication and also induce positive effects on host respiratory system including bronchodilation and mucus lysis. At present, only computer-aided docking and few in vitro studies are available which show anti-SARC-CoV-2 activities of EOs. In this review, role of EOs in the prevention and treatment of COVID-19 is discussed. A discussion on possible side effects associated with EOs as well as anti-corona virus claims made by EOs manufacturers are also highlighted. Based on the current knowledge a chemo-herbal (EOs) combination of the drugs could be a more feasible and effective approach to combat this viral pandemic. .........

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https://link.springer.com/article/10.1007/s10787-020-00744-0