A new antiinflammatory agent identified as 8-[C-beta-D-[2-O-(E)-cinnamoyl]glucopyranosyl]-2- [(R)-2-hydroxypropyl]-7-methoxy-5-methylchromone (1) has been isolated from Aloe barbadensis Miller. At a dose of 200 microg/mouse ear, 1 exhibited topical antiinflammatory activity equivalent to 200 microg/ear of hydrocortisone. There was no reduction in thymus weight caused by treatment with 1 for any of the doses tested, while 200 microg/ear of hydrocortisone resulted in a 50% decrease in thymus weight.

Purpose This study evaluated mechanistic diVerences of pralatrexate, methotrexate, and pemetrexed. Methods Inhibition of dihydrofolate reductase (DHFR) was quantiWed using recombinant human DHFR. Cellular uptake and folylpolyglutamate synthetase (FPGS) activity were determined using radiolabeled pralatrexate, methotrexate, and pemetrexed in NCI-H460 non-small cell lung cancer (NSCLC) cells. The tumor growth inhibition (TGI) was assessed using MV522 and NCI-H460 human NSCLC xenografts. Results Apparent K i values for DHFR inhibition were 45, 26, and >200 nM for pralatrexate, methotrexate, and pemetrexed, respectively. A signiWcantly greater percentage of radiolabeled pralatrexate entered the cells and was polyglutamylatated relative to methotrexate or pemetrexed. In vivo, pralatrexate showed superior anti-tumor activity in both NSCLC models, with more eVective dose-dependent TGI in the more rapidly growing NCI-H460 xenografts. Conclusions Pralatrexate demonstrated a distinct mechanistic and anti-tumor activity proWle relative to methotrexate and pemetrexed. Pralatrexate exhibited enhanced cellular uptake and increased polyglutamylation, which correlated with increased TGI in NSCLC xenograft models.

Background/Aim: Alterations of plasma membrane fluidity are characteristic of many diseases but the intentional modulation of membrane fluidity with drugs has been less studied. We examined the therapeutic potential of the membrane fluidizer diethyl azelate (DEA) and related azelates. Materials and Methods: The effects of azelates on plasma membrane fluidity and cell signaling were examined in primary human and murine cells and in vivo. Endpoints were queried using single target and multiplexed immunoassays. Results: Unique membrane-fluidizing properties and biomarker signatures suggest that azelates are not prodrugs. DEA decreased cytokine signaling from pattern recognition receptors in human dendritic cells, disabled membrane attack of cholera toxin in vitro, and prevented immunosuppression by anthrax lethal toxin in vitro and in vivo. In the murine sepsis model, DEA increased survival and reduced organ damage. Conclusion: Azelates represent a new class of drugs, membrane active immunomodulators, which target an innate homeostatic mechanism, adaptive membrane fluidity modulation.

PNT100 is a 24-base, chemically unmodified DNA oligonucleotide sequence that is complementary to a region upstream of the BCL-2 gene. Exposure of tumor cells to PNT100 results in suppression of proliferation and cell death by a process called DNA interference. PNT2258 is PNT100 that is encapsulated in protective amphoteric liposomes developed to efficiently encapsulate the PNT100 oligonucleotide, provide enhanced serum stability, optimized pharmacokinetic properties and antitumor activity of the nanoparticle both in vivo and in vitro. PNT2258 demonstrates broad antitumor activity against BCL-2-driven WSU-DLCL2 lymphoma, highly resistant A375 melanoma, PC-3 prostate, and Daudi-Burkitt’s lymphoma xenografts. The sequence specificity of PNT100 was demonstrated against three control sequences (scrambled, mismatched, and reverse complement) all encapsulated in a lipid formulation with identical particle characteristics, and control sequences did not demonstrate antiproliferative activity in vivo or in vitro. PNT2258 is currently undergoing clinical testing to evaluate safety and antitumor activity in patients with recurrent or refractory non-Hodgkin’s lymphoma and additional studies are planned.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-014-2476-y) contains supplementary material, which is available to authorized users.

Background/Aim: Insulin resistance (IR) is linked to increased risk of cardiovascular disease and cancer. We examined safety and efficacy of the natural product diethyl azelate (DEA) in overweight males with a varying degree of IR. Patients and Methods: Seventeen subjects [age 18-42, hemoglobin A1c (A1c) of 5.2-6.2%] received orally 1 mg/kg DEA daily for 21 days. Blood plasma glucose, insulin and lipid levels were assessed before and after treatment. Results: DEA was well tolerated without hypoglycemia or adverse effects except transient diarrhea (n=1). DEA significantly reduced fasting glucose by 6.06 mg/dl (n=8) and insulin by 37.8% (n=8) in subjects with IR and/or A1c ≥5.6%. Furthermore, it improved cholesterol/HDL, LDL/HDL, and non-cholesterol HDL/HDL by 5.4, 6.5, and 6.6%, respectively in all subjects, and by 8.0, 9.8, and 9.8%, respectively in 9 subjects with A1c ≥5.6%. Conclusion: DEA efficacy correlates with the degree of IR. DEA holds promise as a novel treatment for the management of IR.Azelaic acid and its esters, azelates, occur naturally in plants, animals, and humans. We discovered that the naturally occurring fatty acid ester, diethyl azelate (DEA) (1), can be used for the treatment of diet-and ethanol-induced insulin resistance (IR), the hallmark of metabolic syndrome, prediabetes and Type 2 diabetes (T2D). A number of studies (2-4) have shown a correlation of metabolic diseases with increased risk of cancer, especially liver, pancreatic and endometrial (5-7).The Western diet combined with a sedentary lifestyle results in chronic metabolic inflammation (8,9). A diet 1173 This article is freely accessible online.

The structure of the plasma membrane affects its function. Changes in membrane fluidity with concomitant effects on membrane protein activities and cellular communication often accompany the transition from a healthy to a diseased state. Although deliberate modulation of membrane fluidity with drugs has not been exploited to date, the latest data suggest the "druggability" of the membrane. Azelaic acid esters (azelates) modulate plasma membrane fluidity and exhibit a broad range of immunomodulatory effects in vitro and in vivo. Azelates represent a new class of drugs, membrane active immunomodulators (MAIMs), which use the entire plasma membrane as the target, altering the dynamics of an innate feedback regulated homeostatic system, adaptive membrane fluidity modulation (AMFM). A review of the literature data spanning >200 years supports the notion that molecules in the MAIMs category including known drugs do exert immunomodulatory effects that have been either neglected or dismissed as off-target effects.A literature search was conducted using PUBMED, MEDLINE, and Library of Congress databases to capture peer-reviewed research articles (including reviews and metaanalyses), published through August 27, 2021, with the earliest record dating from 1801. The search terms included "plasma membrane" AND "fluidity" OR "plasticity" OR "rigidity". Secondary searches combined keywords consisting of individual chemical entities listed in this manuscript (for example, cholesterol, ethanol, turpentine) and physiological conditions (for example pain, fever, disease). The collected abstracts and/or full papers were surveyed by both authors in order to confirm article relevancy to the topic.

No abstract

Azelaic acid and its esters, the azelates, occur naturally in organisms ranging from plants to humans. We have shown that diethyl azelate (DEA) exhibits a broad range of immunomodulatory activities in vitro and in vivo, and mitigates insulin resistance. To further investigate the therapeutic utility of DEA, we evaluated its mutagenicity in Salmonella typhimurium strains, examined metabolism of DEA in rat, dog, monkey and human primary hepatocytes and in human saliva, determined pharmacokinetics of DEA after an oral dose in rats, and queried its physicochemical properties for drug-like characteristics. DEA was not mutagenic in bacterial strains ± rat liver metabolic activation system S-9. It was chemically unstable in hepatocyte culture medium with a half-life of <1 h and was depleted by the hepatocytes in <5 min, suggesting rapid hepatic metabolism. DEA was also quickly degraded by human saliva in vitro. After an oral administration of DEA to rats, the di- and monoester were undetectable in plasma while the levels of azelaic acid increased over time, reached maximum at <2 h, and declined rapidly thereafter. The observed pharmacological properties of DEA suggest that it has value both as a drug or a nutritional supplement.