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Mediators of Inflammation 2018cells transfected with MHC class I and a number of costimulation molecules including B7.1, ICAM, LFA-3, and CD70 are potent antigen-presenting cells (APCs) for the...
cells transfected with MHC class I and a number of costimulation molecules including B7.1, ICAM, LFA-3, and CD70 are potent antigen-presenting cells (APCs) for the generation of antigen-specific cytotoxic T cells (CTLs) . Using APCs, CTLs specific for melanoma antigens have been generated and adoptively transferred to melanoma patients. However, the recent discovery that cells can carry insect viruses raises the potential risk of APCs transmitting xenogenic viruses to patient CTLs. In this study, we have investigated photoreactive methods to inactivate insect viruses in APC. A clinical grade psoralen compound, 8-MOP (UVADEX) in combination with UVA treatment (5 joules/cm) can be used to inactivate cell viruses. UVADEX treatment is sufficient to inactivate insect viruses but does not affect the expression of MHC class I molecules and costimulation molecules on APCs. In fact, UVADEX treatment prevents APC growth while maintaining APC function. Furthermore, UVADEX-treated APCs maintain or have enhanced APC function as determined by enhanced T cell activation, proliferation, and CTL generation. Thus, the use of UVADEX-treated APCs may provide a valuable tool for immunotherapy to generate tumor antigen-specific CTLs.
Topics: Animals; Antigen-Presenting Cells; Cell Proliferation; Drosophila; Immunotherapy; Methoxsalen; T-Lymphocytes, Cytotoxic
PubMed: 30327581
DOI: 10.1155/2018/4167652 -
Heterocyclic Letters 2018The natural product 8-methoxypsoralen (methoxsalen or 8-MOP) in combination with long wavelength ultraviolet light (UVA, 320-400 nm), also referred to as PUVA therapy,...
The natural product 8-methoxypsoralen (methoxsalen or 8-MOP) in combination with long wavelength ultraviolet light (UVA, 320-400 nm), also referred to as PUVA therapy, is used for the treatment of cutaneous proliferative disorders including psoriasis, vitiligo and mycosis fungoides. The use of 8-MOP () is limited by its poor water solubility and there remains a need to develop more water-soluble psoralens to enhance bioavailability following oral administration of the drug. In the present studies a water-soluble dimethylaminoethyl ether analog of 8-MOP was synthesized and analyzed for biological activity. This analog, (8-[2-(N,N-dimethylamino)ethoxy]-psoralen hydrochloride () [or CAS name: 9-[2-(dimethylamino)ethoxy]-7-furo[3,2-][1]benzopyran-7-one, hydrochloride], was found to be significantly more active than in keratinocyte growth inhibition assays (IC = 12 nM and 130 nM for and , respectively). The partially reduced dihydro derivative of , 8-[2-(N,N-dimethylamino)ethoxy]-4',5'-dihydropsoralen hydrochloride () [or CAS name: 9-[2-(dimethylamino)ethoxy]-2,3-dihydro-7-furo[3,2-][1]benzopyran-7-one, hydrochloride] and the partially reduced 4',5'-dihydro-8-methoxypsoralen () lacking the water-solubilizing side-chain were significantly less active. As inhibitors of keratinocyte growth they ranked as IC = 13,000 nM and 70,000 nM for and , respectively, indicating that an unsaturated furan ring in the psoralen was required for maximal activity. Compound () was found to readily intercalate and damage DNA following UVA light treatment as determined by plasmid DNA nicking and unwinding experiments in neutral and alkaline agarose gels. Taken together, these data demonstrate that a water-soluble dimethylaminoethyl ether psoralen targets DNA, is highly active as a photosensitizer, and may be useful in the treatment of skin diseases involving abnormal keratinocyte proliferation.
PubMed: 33575202
DOI: No ID Found -
European Review For Medical and... Jul 2018To explore the effect of 8-MOP on the blood-brain barrier in mice model of cerebral infarction and the underlying mechanism.
OBJECTIVE
To explore the effect of 8-MOP on the blood-brain barrier in mice model of cerebral infarction and the underlying mechanism.
MATERIALS AND METHODS
Middle cerebral artery occlusion (MCAO) model was established to induce permanent cerebral infarction. The neurological function was observed and scored by the modified longa score method after model establishment. Besides, the water content of brain tissue was measured by the standard dry weight method. Evans blue exudation rate was used to evaluate the effect of 8-MOP on the permeability of the blood-brain barrier. Western-blot and quantitative polymerase chain reaction (qPCR) were used to detect the expression of MMP-9, claudin-5, vascular endothelial growth factor (VEGF), as well as the NFE2-related factor 2 (Nrf-2)/hemeoxygenase 1 (HO-1) pathway.
RESULTS
8-MOP could reduce the neurological deficit scores in a dose-dependent manner, thereby reducing cerebral edema. After 8-MOP treatment, the expression of MMP-9 decreased in ischemic brain tissue, whereas the expression of claudin-5, VEGF, and GFAP increased, suggesting that the blood-brain barrier ultrastructure was improved. In addition, the expression of Nrf-2 and HO-1 decreased after the model establishment of cerebral infarction. However, the expression of Nrf-2 and HO-1 increased in ischemic brain tissue after 8-MOP treatment.
CONCLUSIONS
8-MOP may protect the blood-brain barrier via the Nrf-2/HO-1 pathway.
Topics: Animals; Blood-Brain Barrier; Cerebral Infarction; Disease Models, Animal; Endothelial Cells; Heme Oxygenase-1; Male; Membrane Proteins; Methoxsalen; Mice; NF-E2-Related Factor 2; Permeability; Signal Transduction; Treatment Outcome
PubMed: 30024618
DOI: 10.26355/eurrev_201807_15424 -
Current Biology : CB Jun 2018Defensive variability of crops and natural systems can alter herbivore communities and reduce herbivory [1, 2]. However, it is still unknown how defense variability...
Defensive variability of crops and natural systems can alter herbivore communities and reduce herbivory [1, 2]. However, it is still unknown how defense variability translates into herbivore suppression. Nonlinear averaging and constraints in physiological tracking (also more generally called time-dependent effects) are the two mechanisms by which defense variability might impact herbivores [3, 4]. We conducted a set of experiments manipulating the mean and variability of a plant defense, showing that defense variability does suppress herbivore performance and that it does so through physiological tracking effects that cannot be explained by nonlinear averaging. While nonlinear averaging predicted higher or the same herbivore performance on a variable defense than on an invariable defense, we show that variability actually decreased herbivore performance and population growth rate. Defense variability reduces herbivore performance in a way that is more than the average of its parts. This is consistent with constraints in physiological matching of detoxification systems for herbivores experiencing variable toxin levels in their diet and represents a more generalizable way of understanding the impacts of variability on herbivory [5]. Increasing defense variability in croplands at a scale encountered by individual herbivores can suppress herbivory, even if that is not anticipated by nonlinear averaging.
Topics: Animals; Food Chain; Herbivory; Methoxsalen; Moths; Plants
PubMed: 29887306
DOI: 10.1016/j.cub.2018.04.070 -
Acta Dermato-venereologica Jun 2018The effects of 8-Methoxypsoralen plus ultraviolet A (PUVA) or ultraviolet B (UVB) alone on imiquimod-induced psoriasis were examined in a mouse model. Mouse skin was...
The effects of 8-Methoxypsoralen plus ultraviolet A (PUVA) or ultraviolet B (UVB) alone on imiquimod-induced psoriasis were examined in a mouse model. Mouse skin was treated with repetitive sub-phototoxic doses of PUVA or UVB before or during the induction of toll-like receptor 7/8 activation and psoriasis through the application of imiquimod. PUVA, to a greater degree than UVB, suppressed the established imiquimod-induced psoriatic phenotype, but pretreatment with PUVA prior to administration of imiquimod also reduced the susceptibility of murine skin to respond to imiquimod to a greater degree than did pretreatment with UVB. PUVA downregulated baseline levels of miRNA27a and 29a, as well as interferon-γ, interleukin-17 and -9, cytokines, which drive psoriatic inflammation. Microarray analysis showed enrichment of senescence pathway genes linked to upregulation of p16/p21 proteins after PUVA pretreatment. However, the anti-psoriatic effect of PUVA was lost when there was an interval of 7 days between final exposure to PUVA and the start of administration of imiquimod. This indicated that (UVB and) PUVA diminished imiquimod-induced established psoriatic inflammation, but also primed the skin in favour of a reduced responsiveness to toll-like receptor activation.
Topics: Aminoquinolines; Animals; Cytokines; Disease Models, Animal; Female; Gene Expression Regulation; Imiquimod; Methoxsalen; Mice, Inbred BALB C; PUVA Therapy; Photosensitizing Agents; Psoriasis; Signal Transduction; Skin; Time Factors
PubMed: 29582898
DOI: 10.2340/00015555-2905 -
Anais Brasileiros de Dermatologia 2017Pigmented purpuric dermatoses are chronic vascular inflammatory conditions characterized by the presence of pigmented macules. Among its different presentations, lichen...
Pigmented purpuric dermatoses are chronic vascular inflammatory conditions characterized by the presence of pigmented macules. Among its different presentations, lichen aureus is distinguished by the lichenoid conformation of its plaques and the predilection for lower limb involvement. Its segmented form is rare and difficult to control, especially in cases of symptomatic lesions. We report a rare case of segmental lichen aureus with six years of evolution associated with light itching. We also discuss the main therapeutic approaches to control the disease.
Topics: Betamethasone; Female; Glucocorticoids; Humans; Lichenoid Eruptions; Methoxsalen; Middle Aged; Photosensitizing Agents; Sunlight
PubMed: 29166512
DOI: 10.1590/abd1806-4841.20174781 -
Indian Journal of Ophthalmology Nov 2017Psoralen compounds such as methoxsalen are photosensitizer agents used in conjunction with ultraviolet A (UVA) radiation exposure as photochemotherapy (Psoralens and...
Psoralen compounds such as methoxsalen are photosensitizer agents used in conjunction with ultraviolet A (UVA) radiation exposure as photochemotherapy (Psoralens and ultraviolet-A therapy [PUVA therapy]) for certain epidermal skin disorders such as psoriasis and vitiligo. Methoxsalen has been shown to be associated with premature cataract formation by forming adducts with lens proteins following oral administration and subsequent UVA exposure. Hence, the use of UV-filtering glasses is recommended during PUVA therapy sessions. Ocular tissues can be exposed to its photosensitizing effect with subsequent UV radiation exposure through sunlight if the patient was to be without protective eye glasses, potentially causing macular toxicity. Till date, there have been no reports in the literature of any posterior segment ocular toxicity arising from methoxsalen use. Here, we describe a case of a bilateral macular toxicity in a middle-aged male treated with methoxsalen for vitiligo.
Topics: Electrooculography; Electroretinography; Humans; Macula Lutea; Male; Methoxsalen; Middle Aged; Photosensitizing Agents; Retinal Diseases; Retinal Pigment Epithelium; Visual Acuity; Vitiligo
PubMed: 29133667
DOI: 10.4103/ijo.IJO_413_17 -
Toxicology and Applied Pharmacology Dec 2017Furanocoumarins derived from herbal and citrus extracts can act as antibacterial, antioxidant, immunomodulator, apoptotic, and selective anticancer agents, prompting a...
Furanocoumarins derived from herbal and citrus extracts can act as antibacterial, antioxidant, immunomodulator, apoptotic, and selective anticancer agents, prompting a biological investigation to determine and predict their clinical therapeutic significance. Here, the cell cytotoxic effects of bergapten and xanthotoxin were analyzed alone and in combination with standard chemotherapeutics on three multidrug resistant cells and their nonresistant parental counterparts. The furanocoumarins modulatory effects on MDR1, BCRP, and MRP pump expression and function were investigated. Although quantitative real time PCR demonstrated that the MDR transcript level changes in a time dependent manner, flow cytometric analyses using fluorescent-labeled antibodies have indicated that bergapten and xanthotoxin had no significant effect on the protein levels. FACS analyses indicated that these prominent anticancer agents significantly blocked MDR1, BCRP, and MRP transporter function. Maximum furanocoumarin-mediated pump activity blockage in the MDR-resistant cells was quantified as 87% of normal and consequently, chemotherapeutic accumulation increased up to 2.7-fold and cytotoxicity tension increased 104-fold. MDR1 efflux kinetics also revealed that the maximum velocity and the pump affinity to daunorubicin were uncompetitively decreased. We conclude that bergapten and xanthotoxin are cytotoxic agents capable of preventing daunorubicin, mitoxantrone, and cisplatin binding to ABC-transporters and subsequently inhibiting their efflux out of cells and they may be a potential combination therapy for malignant cancers.
Topics: 5-Methoxypsoralen; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Antineoplastic Agents, Phytogenic; Cell Proliferation; Cell Survival; Cisplatin; Daunorubicin; Dose-Response Relationship, Drug; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Kinetics; MCF-7 Cells; Methoxsalen; Mitoxantrone; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Neoplasm Proteins; Neoplasms
PubMed: 29079042
DOI: 10.1016/j.taap.2017.10.018 -
Pharmacognosy Magazine Jul 2017Coumarins exert many biological effects in humans, animals, and plants, which make the evaluation of their biological activities and study of their role in ethnomedicine...
INTRODUCTION
Coumarins exert many biological effects in humans, animals, and plants, which make the evaluation of their biological activities and study of their role in ethnomedicine highly valued.
OBJECTIVES
Here, we selected seven plants which have ethnopharmacological use as antimicrobial in Iraq and the aims were to quantify the two structural isomers bergapten and methoxsalen in their seeds, to evaluate the antibacterial activities against several clinical isolates, and to isolate bergapten and methoxsalen from .
MATERIALS AND METHODS
Seven plants were extracted by petroleum ether (PE) and ethanol (EtOH). Bergapten and methoxsalen were separated and purified by preparative thin-layer chromatography. Quantification of the furanocoumarins has been conducted by high-performance liquid chromatography, and all the plant extracts and pure compounds were checked for antibacterial activities utilizing alamar blue microplate assay.
RESULTS
was deprived of bergapten and methoxsalen and methoxsalen was not detected from . Bergapten was abundant in PE more than in EtOH; on the other hand, EtOH was rich in methoxsalen. The separation of the two structural isomers was performed using normal phase chromatography and ultraviolet light as an indicator. All extracts showed weak to moderate antibacterial activities against Gram-positive isolates which were more sensitive than the negative ones. extract was least active, uncover the antibacterial role of bergapten and methoxsalen.
CONCLUSION
These findings support the medicinal use of seeds of seven plants from family and quantify the two pharmacologically important furanocoumarins (bergapten and methoxsalen).
SUMMARY
This study was conducted to evaluate the antibacterial activities of seven plants seeds used in local medicine in Iraq. High-performance liquid chromatography was used to quantify bergapten and xanthotoxin in non-polar and polar extracts of these seeds. This study supports the medicinal use of these plants and clarifies the role of bergapten and xanthotoxin in antibacterial activities of these plants. EtOH: Ethanol; MIC: Minimum inhibitory concentration; PE: Petroleum ether; Rf: Retardation factor; Rt: Retention time.
PubMed: 28808379
DOI: 10.4103/pm.pm_503_16 -
The Cochrane Database of Systematic... Aug 2017Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization guidelines for... (Review)
Review
BACKGROUND
Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization guidelines for pharmacological treatments for children's persisting pain acknowledge that pain in children is a major public health concern of high significance in most parts of the world. While in the past pain was largely dismissed and was frequently left untreated, views on children's pain have changed over time, and relief of pain is now seen as important.We designed a suite of seven reviews on chronic non-cancer pain and cancer pain (looking at antidepressants, antiepileptic drugs, non-steroidal anti-inflammatory drugs, opioids, and paracetamol) in order to review the evidence for children's pain utilising pharmacological interventions.As the leading cause of morbidity in the world today, chronic disease (and its associated pain) is a major health concern. Chronic pain (that is pain lasting three months or longer) can arise in the paediatric population in a variety of pathophysiological classifications (nociceptive, neuropathic, or idiopathic) from genetic conditions, nerve damage pain, chronic musculoskeletal pain, and chronic abdominal pain, as well as for other unknown reasons.Non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat pain, reduce fever, and for their anti-inflammation properties. They are commonly used within paediatric pain management. Non-steroidal anti-inflammatory drugs are currently licensed for use in Western countries, however they are not approved for infants under three months old. The main adverse effects include renal impairment and gastrointestinal issues. Common side effects in children include diarrhoea, headache, nausea, constipation, rash, dizziness, and abdominal pain.
OBJECTIVES
To assess the analgesic efficacy and adverse events of NSAIDs used to treat chronic non-cancer pain in children and adolescents aged between birth and 17 years, in any setting.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online, MEDLINE via Ovid, and Embase via Ovid from inception to 6 September 2016. We also searched the reference lists of retrieved studies and reviews, as well as online clinical trial registries.
SELECTION CRITERIA
Randomised controlled trials, with or without blinding, of any dose and any route, treating chronic non-cancer pain in children and adolescents, comparing any NSAID with placebo or an active comparator.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed studies for eligibility. We planned to use dichotomous data to calculate risk ratio and number needed to treat for one additional event, using standard methods. We assessed GRADE and created three 'Summary of findings' tables.
MAIN RESULTS
We included seven studies with a total of 1074 participants (aged 2 to 18 years) with chronic juvenile polyarthritis or chronic juvenile rheumatoid arthritis. All seven studies compared an NSAID with an active comparator. None of the studies were placebo controlled. No two studies investigated the same type of NSAID compared with another. We were unable to perform a meta-analysis.Risk of bias varied. For randomisation and allocation concealment, one study was low risk and six studies were unclear risk. For blinding of participants and personnel, three studies were low risk and four studies were unclear to high risk. For blinding of outcome assessors, all studies were unclear risk. For attrition, four studies were low risk and three studies were unclear risk. For selective reporting, four studies were low risk, two studies were unclear risk, and one study was high risk. For size, three studies were unclear risk and four studies were high risk. For other potential sources of bias, seven studies were low risk. Primary outcomesThree studies reported participant-reported pain relief of 30% or greater, showing no statistically significant difference in pain scores between meloxicam and naproxen, celecoxib and naproxen, or rofecoxib and naproxen (P > 0.05) (low-quality evidence).One study reported participant-reported pain relief of 50% or greater, showing no statistically significant difference in pain scores between low-dose meloxicam (0.125 mg/kg) and high-dose meloxicam (0.25 mg/kg) when compared to naproxen 10 mg/kg (P > 0.05) (low-quality evidence).One study reported Patient Global Impression of Change, showing 'very much improved' in 85% of ibuprofen and 90% of aspirin participants (low-quality evidence). Secondary outcomesAll seven studies reported adverse events. Participants reporting an adverse event (one or more per person) by drug were: aspirin 85/202; fenoprofen 28/49; ibuprofen 40/45; indomethacin 9/30; ketoprofen 9/30; meloxicam 18/47; naproxen 44/202; and rofecoxib 47/209 (very low-quality evidence).All seven studies reported withdrawals due to adverse events. Participants withdrawn due to an adverse event by drug were: aspirin 16/120; celecoxib 10/159; fenoprofen 0/49; ibuprofen 0/45; indomethacin 0/30; ketoprofen 0/30; meloxicam 10/147; naproxen 17/285; and rofecoxib 3/209 (very low-quality evidence).All seven studies reported serious adverse events. Participants experiencing a serious adverse event by drug were: aspirin 13/120; celecoxib 5/159; fenoprofen 0/79; ketoprofen 0/30; ibuprofen 4/45; indomethacin 0/30; meloxicam 11/147; naproxen 10/285; and rofecoxib 0/209 (very low-quality evidence).There were few or no data for our remaining secondary outcomes: Carer Global Impression of Change; requirement for rescue analgesia; sleep duration and quality; acceptability of treatment; physical functioning as defined by validated scales; and quality of life as defined by validated scales (very low-quality evidence).We rated the overall quality of the evidence (GRADE rating) for our primary and secondary outcomes as very low because there were limited data from studies and no opportunity for a meta-analysis.
AUTHORS' CONCLUSIONS
We identified only a small number of studies, with insufficient data for analysis.As we could undertake no meta-analysis, we are unable to comment about efficacy or harm from the use of NSAIDs to treat chronic non-cancer pain in children and adolescents. Similarly, we cannot comment on our remaining secondary outcomes: Carer Global Impression of Change; requirement for rescue analgesia; sleep duration and quality; acceptability of treatment; physical functioning; and quality of life.We know from adult randomised controlled trials that some NSAIDs, such as ibuprofen, naproxen, and aspirin, can be effective in certain chronic pain conditions.
Topics: Adolescent; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Juvenile; Arthritis, Rheumatoid; Aspirin; Celecoxib; Child; Child, Preschool; Chronic Disease; Chronic Pain; Fenoprofen; Humans; Ibuprofen; Lactones; Meloxicam; Methoxsalen; Naproxen; Randomized Controlled Trials as Topic; Sulfones; Thiazines; Thiazoles
PubMed: 28770976
DOI: 10.1002/14651858.CD012537.pub2