Up to now the lipid bilayers were rarely considered as targets in cancer therapy despite pronounced differences in lipid composition between plasma membranes of benign and malignant cells. In this study we demonstrate that the lipid bilayer of the plasma membrane is druggable and suitable for facilitating selective delivery of amphiphilic gemcitabine-squalene nanomedicines to cancer cells. Data from radioactive assays, fluorescent membrane probes and molecular dynamics simulations provide evidence of selective accumulation of gemcitabine-squalene in the plasma membranes with disrupted lipid asymmetry and its subsequent preferential uptake by malignant cells. This causes pronounced cytotoxicity on cancer cells in comparison to their benign counterparts originating from the same tissue.
The growing interest in foods that can be beneficial to human health is bringing into focus some products that have been used locally for centuries but have recently gained worldwide attention. One of these foods is pumpkin seed oil, which has been used in culinary and traditional medicine, but recent data also show its use in the pharmaceutical and cosmetic industries. In addition, some sources refer to it as a potential functional food, mainly because it is obtained from pumpkin seeds, which contain many functional components. However, the production process of the oil may affect the content of these components and consequently the biological activity of the oil. In this review, we have focused on summarizing scientific data that explore the potential of pumpkin seed oil as a functional food ingredient. We provide a comprehensive overview of pumpkin seed oil chemical composition, phytochemical content, biological activity, and safety, as well as the overview of production processes and contemporary use. The main phytochemicals in pumpkin seed oil with health-related properties are polyphenols, phytoestrogens, and fatty acids, but carotenoids, squalene, tocopherols, and minerals may also contribute to health benefits. Most studies have been conducted in vitro and support the claim that pumpkin seed oil has antioxidant and antimicrobial activities. Clinical studies have shown that pumpkin seed oil may be beneficial in the treatment of cardiovascular problems of menopausal women and ailments associated with imbalance of sex hormones.
- MeSH
- antiinfekční látky * MeSH
- antioxidancia farmakologie MeSH
- Cucurbita * chemie MeSH
- funkční potraviny MeSH
- fytoestrogeny MeSH
- fytonutrienty MeSH
- karotenoidy MeSH
- léčivé přípravky MeSH
- lidé MeSH
- mastné kyseliny chemie MeSH
- oleje rostlin chemie farmakologie MeSH
- polyfenoly MeSH
- přísady do jídla * MeSH
- skvalen MeSH
- tokoferoly MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
BACKGROUND: The absolute degree of protection from influenza vaccines in older adults has not been studied since 2001. This study aimed to show the clinical efficacy of an MF59-adjuvanted quadrivalent influenza vaccine (aQIV) in adults 65 years or older compared with adults not vaccinated to prevent influenza. METHODS: We did a randomised, stratified, observer-blind, controlled, multicentre, phase 3 study at 89 sites in 12 countries in 2016-17 northern hemisphere and 2017 southern hemisphere influenza seasons. We enrolled community-dwelling male and female adults aged 65 years and older who were healthy or had comorbidities that increased their risk of influenza complications. We stratified eligible participants by age (cohorts 65-74 years and ≥75 years) and risk of influenza complications (high and low) and randomly assigned them (1:1) via an interactive response technology to receive either aQIV or a non-influenza comparator vaccine. We masked participants and outcome assessors to the administered vaccine. Personnel administering the vaccines did not participate in endpoint assessment. The primary outcome was absolute vaccine efficacy assessed by RT-PCR-confirmed influenza due to any influenza strain in the overall study population (full analysis set) from day 21 to 180 or the end of the influenza season. Vaccine efficacy was calculated on the basis of a Cox proportional hazard regression model for time to first occurrence of RT-PCR-confirmed influenza due to any strain of influenza. Safety outcomes were assessed in the overall study population. This trial was registered with ClinicalTrials.gov, NCT02587221. FINDINGS: Northern hemisphere enrolment occurred between Sept 30, 2016, and Feb 28, 2017, and southern hemisphere enrolment between May 26, 2017, and 30 June 30, 2017. aQIV was administered to 3381 participants, who subsequently had 122 (3·6%) RT-PCR-confirmed influenza cases, and the comparator was administered to 3380 participants, who subsequently had 151 (4·5%) influenza cases. The majority, 214 (78·4%) of 273, were caused by influenza A H3N2. Most antigenically characterised isolates were mismatched to the vaccine strain (118 [85%] of 139). Vaccine efficacy was 19·8% (multiplicity-adjusted 95% CI -5·3 to 38·9) against all influenza and 49·9% (-24·0 to 79·8) against antigenically matched strains, when the protocol definition of influenza-like illness was used. The most common local solicited adverse event was injection site pain, reported by 102 (16·3%) of 624 participants in the aQIV group and 71 (11·2%) of 632 of participants in the comparator group. Deaths were evenly distributed; none were considered related to study vaccines. The safety profile for aQIV was similar to previously reported trials. INTERPRETATION: The prespecified criterion for showing the efficacy of aQIV in older adults was not met during the influenza seasons with high amounts of vaccine strain mismatch. Vaccine efficacy was higher against influenza cases associated with higher fever, which represent more clinically significant disease. FUNDING: Seqirus UK.
- MeSH
- adjuvancia imunologická aplikace a dávkování MeSH
- chřipka lidská prevence a kontrola MeSH
- lidé MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- polysorbáty * MeSH
- rizikové faktory MeSH
- roční období * MeSH
- senioři MeSH
- skvalen * MeSH
- vakcíny proti chřipce aplikace a dávkování MeSH
- virus chřipky A, podtyp H3N2 imunologie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
Squalene is a naturally occurring triterpene with wide industrial applications. Due to limited natural resources, production of this valuable lipid in yeast is of high commercial relevance. Typically low levels of squalene in yeast can be significantly increased by specific cultivation conditions or genetic modifications. Under normal conditions, excess squalene is stored in lipid droplets (LD), while in a Saccharomyces cerevisiae mutant unable to form LD it is distributed to cellular membranes. We present here the evidence that squalene accumulation in this LD-less mutant treated with squalene monooxygenase inhibitor terbinafine induces growth defects and loss of viability. We show that plasma membrane malfunction is involved in squalene toxicity. We have found that subinhibitory concentrations of terbinafine increased the sensitivity of LD-less mutant to several membrane-active substances. Furthermore, squalene accumulation in terbinafine-treated LD-less cells disturbed the maintenance of membrane potential and increased plasma membrane permeability to rhodamine 6G. LD-less cells treated with terbinafine showed also high sensitivity to osmotic stress. To confirm the causal relationship between squalene accumulation, loss of viability and impaired plasma membrane functions we treated LD-less cells simultaneously with terbinafine and squalene synthase inhibitor zaragozic acid. Reduction of squalene levels by zaragozic acid improved cell growth and viability and decreased plasma membrane permeability to rhodamine 6G in terbinafine-treated LD-less cells. Our results support the hypothesis that plasma membrane malfunction is involved in the mechanisms of squalene lipotoxicity in yeast cells with defective lipid storage.
- MeSH
- adjuvancia imunologická * chemie MeSH
- dítě MeSH
- dospělí MeSH
- formaldehyd MeSH
- konzervační prostředky farmaceutické MeSH
- lidé MeSH
- maximální přípustná koncentrace MeSH
- nežádoucí účinky léčiv MeSH
- skvalen terapeutické užití MeSH
- sloučeniny hliníku farmakologie terapeutické užití MeSH
- thimerosal farmakologie MeSH
- vakcinace MeSH
- vakcíny chemie MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
Squalene is a natural triterpenoid present virtually in all taxonomic groups. Its use for improving human health is rooted in ancient human history as several Pacific nations consumed the oil from livers of deep-sea sharks with high squalene content to improve their health and extend the life. In addition to the use as nutritional supplement, this molecule finds today many applications in pharmacology and cosmetics, or as a valuable industrial lubricant. Broad application potential of squalene is related to its physico-chemical characteristics, antioxidant activity and to its ability to interact with cell membranes. The industrial use of squalene is limited by short natural resources. Even today squalene is acquired mainly from shark liver oil; however, this source is no more tenable from the environmental viewpoint. Plant sources (e.g. olives, amaranth seeds) and particularly microbial production are thus gaining importance as promising alternatives for extended industrial use of squalene.
- MeSH
- biotechnologie MeSH
- skvalen * farmakologie chemická syntéza chemie terapeutické užití MeSH
- Publikační typ
- práce podpořená grantem MeSH
In this study we describe the immunogenicity results from a subset of older people (N = 5187) who participated in a Phase 3 randomized, observer-blinded trial of AS03-TIV versus TIV (Fluarix™) (ClinicalTrials.gov, NCT00753272). Participants received one dose of AS03-TIV or TIV in each study year and antibody titers against the vaccine strains were assessed using hemagglutination-inhibition (HI) assay at 21 d and 180 d post-vaccination in each vaccine group in the 2008/09 (Year 1) and 2009/10 (Year 2) influenza seasons. Manufacturing consistency of 3 lots of AS03-TIV for HI antibody responses in Year 1 was a co-primary objective. In a post-hoc analysis, a statistical regression model included 4830 subjects in whom immunogenicity and laboratory-confirmed attack rate data were available; the analysis was performed to assess HI antibody titers against A/H3N2 as a correlate of protection for laboratory-confirmed A/H3N2 influenza. AS03-TIV and TIV elicited strong HI antibody responses against each vaccine strain 21 d post-vaccination in both years. The manufacturing consistency of 3 lots of AS03-TIV was demonstrated. In both years and each vaccine group, HI antibody responses were lower for A/H1N1 than the other vaccine strains. Day 180 seroconversion rates (proportion with ≥4-fold increase in titer compared with pre-vaccination titer) in Year 1 in the AS03-TIV and TIV groups, respectively, were 87.7% and 74.1% for A/H3N2, 69.7% and 59.6% for influenza B, and 58.3% and 47.4% for A/H1N1. The post-hoc statistical model based on A/H3N2 attack rates and HI antibody titers estimated that a 4-fold increase in post-vaccination titers against A/H3N2 was associated with a 2-fold decrease in the odds of A/H3N2 infection.
- MeSH
- alfa-tokoferol aplikace a dávkování MeSH
- chřipka lidská prevence a kontrola virologie MeSH
- fixní kombinace léků MeSH
- inaktivované vakcíny aplikace a dávkování imunologie MeSH
- jednoduchá slepá metoda MeSH
- lidé MeSH
- polysorbáty aplikace a dávkování MeSH
- protilátky virové krev MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- skvalen aplikace a dávkování MeSH
- testy inhibice hemaglutinace MeSH
- vakcíny proti chřipce aplikace a dávkování imunologie MeSH
- virus chřipky A, podtyp H3N2 imunologie MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- srovnávací studie MeSH
- MeSH
- biologické markery analýza krev metabolismus MeSH
- cholesteny analýza MeSH
- cholesterol * analogy a deriváty analýza biosyntéza chemie MeSH
- diabetes mellitus 1. typu * komplikace metabolismus MeSH
- dieta s omezením sacharidů MeSH
- dospělí MeSH
- fytosteroly analýza MeSH
- glykovaný hemoglobin analýza MeSH
- HDL-cholesterol analýza MeSH
- hmotnostní úbytek * fyziologie MeSH
- LDL-cholesterol analýza MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- obezita * MeSH
- odběr biologického vzorku MeSH
- programy na snížení hmotnosti MeSH
- prospektivní studie MeSH
- redukční dieta MeSH
- senioři MeSH
- skvalen analýza MeSH
- triglyceridy analýza MeSH
- vysokoúčinná kapalinová chromatografie metody využití MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- klinické zkoušky MeSH
- práce podpořená grantem MeSH
- MeSH
- adjuvancia farmaceutická MeSH
- antioxidancia MeSH
- beta-karoten * MeSH
- časové faktory MeSH
- emulze chemie MeSH
- farmaceutická technologie MeSH
- lipidové peroxidy analýza MeSH
- příprava léků MeSH
- skvalen MeSH
- stabilita léku * MeSH
- vakcína proti vzteklině * chemie MeSH
- velikost částic MeSH
- Publikační typ
- práce podpořená grantem MeSH
Aniž si to uvědomujeme, látky s adjuvantním efektem ovlivňují náš imunitní systém trvale. Jedná se jednak o látky přírodního původu včetně všudypřítomných mikrobiálních antigenů s adjuvantním efektem a jednak o chemicky syntetizované látky. Přesný mechanizmus účinku adjuvancií a ovlivnění funkce imunitního systému není zcela objasněn. Protože existuje potenciální riziko, že by některé látky s adjuvantním efektem mohly být jedním z faktorů znepokojujícího nárůstu zánětlivých a autoimunitních chorob, je diskuse o jejich dlouhodobé bezpečnosti ve veřejném zájmu.
Without us even realising it, substances with adjuvant effects act on our immune systems all the time. These are firstly natural substances, including ubiquitous microbial antigens with adjuvant effects and secondly chemically synthesised substances. The exact mechanism of action of adjuvant substances and their effects on the function of the immune system is not fully understood. Because there is a potential risk that some substances with adjuvant effects could be one of the factors behind the disturbing increase in inflammatory and autoimmune diseases, discussion about their long-term safety definitely in public interest.
- Klíčová slova
- syndrom ASIA,
- MeSH
- adjuvancia imunologická * aplikace a dávkování klasifikace škodlivé účinky terapeutické užití MeSH
- autoimunita * fyziologie účinky léků MeSH
- autoimunitní nemoci epidemiologie etiologie chemicky indukované MeSH
- hliník škodlivé účinky MeSH
- imunitní systém - jevy fyziologie účinky léků MeSH
- lidé MeSH
- myši MeSH
- nebezpečné látky škodlivé účinky toxicita MeSH
- silikony škodlivé účinky MeSH
- skvalen škodlivé účinky terapeutické užití MeSH
- vakcíny analýza škodlivé účinky MeSH
- virům podobné částice škodlivé účinky terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- přehledy MeSH
