18 research outputs found
Effect of a regular consumption of traditional and roasted oat and barley flakes on blood lipids and glucose metabolismâA randomized crossover trial
Background Regular consumption of the soluble dietary fiber ÎČ-glucan is associated with decreased total cholesterol (TC), low-density lipoprotein (LDL) cholesterol and blood glucose. Barley and oat flakes as natural sources of ÎČ-glucan were roasted to improve sensory quality. The aim of this study was to investigate whether roasting of barley and oat flakes changes the physiological impact of the ÎČ-glucan-rich flakes on glucose and lipid metabolism. Method A five-armed randomized crossover trial design was used. The intervention study was conducted from May 2018 to May 2019 and included 32 healthy subjects with moderately increased LDL cholesterol (â„2.5 mmol/L). During the 3-week intervention periods, 80 g of roasted or traditional barley or oat flakes, or four slices of white toast bread per day were consumed for breakfast. At the start and the end of each intervention, fasting and postprandial blood was taken. The intervention periods were separated by 3-week wash-out periods. Results During the interventions with the cereal flakes, TC and LDL cholesterol concentrations were significantly reduced compared to baseline values by mean differences of 0.27â0.33 mmol/L and 0.21â0.30 mmol/L, respectively ( p < 0.05), while high-density lipoprotein (HDL) cholesterol was only reduced after the intervention with barley flakes ( p < 0.05). After the intervention period with toast, TC and HDL cholesterol increased ( p < 0.05). The fasting levels of triglycerides, fasting blood glucose and insulin did not change in any group. The effects of traditional and roasted varieties on blood lipids did not differ between the groups. Conclusion The regular consumption of traditional or roasted barley and oat flakes contributes to the management of cardiovascular diseases by improving TC and LDL cholesterol. Clinical trial registration https://clinicaltrials.gov/ct2/show/NCT03648112 , identifier NCT03648112
BRP-187: A potent inhibitor of leukotriene biosynthesis that acts through impeding the dynamic 5-lipoxygenase/5-lipoxygenase-activating protein (FLAP) complex assembly
The pro-inflammatory leukotrienes (LTs) are formed from arachidonic acid (AA) in activated leukocytes, where 5-lipoxygenase (5-LO) translocates to the nuclear envelope to assemble a functional complex with the integral nuclear membrane protein 5-LO-activating protein (FLAP). FLAP, a MAPEG family member, facilitates AA transfer to 5-LO for efficient conversion, and LT biosynthesis critically depends on FLAP. Here we show that the novel LT biosynthesis inhibitor BRP-187 prevents the 5-LO/FLAP interaction at the nuclear envelope of human leukocytes without blocking 5-LO nuclear redistribution. BRP-187 inhibited 5-LO product formation in human monocytes and polymorphonuclear leukocytes stimulated by lipopolysaccharide plus N-formyl-methionyl-leucyl-phenylalanine (IC50=7-10nM), and upon activation by ionophore A23187 (IC50=10-60nM). Excess of exogenous AA markedly impaired the potency of BRP-187. Direct 5-LO inhibition in cell-free assays was evident only at >35-fold higher concentrations, which was reversible and not improved under reducing conditions. BRP-187 prevented A23187-induced 5-LO/FLAP complex assembly in leukocytes but failed to block 5-LO nuclear translocation, features that were shared with the FLAP inhibitor MK886. Whereas AA release, cyclooxygenases and related LOs were unaffected, BRP-187 also potently inhibited microsomal prostaglandin E2 synthase-1 (IC50=0.2ÎŒM), another MAPEG member. In vivo, BRP-187 (10mg/kg) exhibited significant effectiveness in zymosan-induced murine peritonitis, suppressing LT levels in peritoneal exudates as well as vascular permeability and neutrophil infiltration. Together, BRP-187 potently inhibits LT biosynthesis in vitro and in vivo, which seemingly is caused by preventing the 5-LO/FLAP complex assembly and warrants further preclinical evaluation
Sex differences in prostaglandin biosynthesis in neutrophils during acute inflammation
The severity and course of inflammatory processes differ between women and men, but the biochemical mechanisms underlying these sex differences are elusive. Prostaglandins (PG) and leukotrienes (LT) are lipid mediators linked to inflammation. We demonstrated superior LT biosynthesis in human neutrophils and monocytes, and in mouse macrophages from females, and we confirmed these sex differences in vivo where female mice produced more LTs during zymosan-induced peritonitis versus males. Here, we report sex differences in PG production in neutrophils during acute inflammation. In the late phase (4-8âhrs) of mouse zymosan-induced peritonitis and rat carrageenan-induced pleurisy, PG levels in males were higher versus females, seemingly due to higher PG production in infiltrated neutrophils. Accordingly, human neutrophils from males produced more PGE2 than cells from females. Increased PG biosynthesis in males was accompanied by elevated cyclooxygenase (COX)-2 expression connected to increased nuclear factor-kappa B activation, and was abolished when LT synthesis was pharmacologically blocked, suggesting that elevated PG production in males might be caused by increased COX-2 expression and by shunting phenomena due to suppressed LT formation. Conclusively, our data reveal that the biosynthesis of pro-inflammatory PGs and LTs is conversely regulated by sex with consequences for the inflammatory response
Humudifucol and bioactive prenylated polyphenols from hops (Humulus lupulus cv. "Cascade")
Humulus lupulus (hop plant) has long been used in traditional medicine as a sedative and antimicrobial agent. More recently, attention has been devoted to the phytoestrogenic activity of the plant extracts as well as to the antiinflammatory and chemopreventive properties of the prenylated chalcones present. In this study, an Italian sample of H. lupulus cv. âCascadeâ has been investigated and three new compounds [4-hydroxycolupulone (6), humudifucol (7) and cascadone (8)] have been purified and identified by means of NMR spectroscopy along with four known metabolites. Notably, humudifucol (7) is
the first prenylated dimeric phlorotannin discovered in nature. Because structurally related phloroglucinols from natural sources were found previously to inhibit microsomal prostaglandin E2 synthase (mPGES)-1 and 5-lipoxygenase (5-LO), the isolated compounds were evaluated for their bioactivity against these pro-inflammatory target proteins. The prenylated chalcone xanthohumol inhibited both enzymes at low ÎŒM concentrations
Selective upregulation of TNFα expression in classically-activated human monocyte-derived macrophages (M1) through pharmacological interference with V-ATPase.
Pharmacological interference with vacuolar-type H(+)-ATPase (V-ATPase), a proton-translocating enzyme involved in protein transport and pH regulation of cell organelles, is considered a potential strategy for cancer therapy. Macrophages are critically involved in tumor progression and may occur as pro-tumoral M2 phenotype, whereas classically-activated M1 can inhibit tumor development for example by releasing tumor-suppressing molecules, including tumor necrosis factor (TNF)α. Here, we show that targeting V-ATPase by selective inhibitors such as archazolid upregulates the expression and secretion of TNFα in lipopolysaccharide (LPS)- or LPS/interferon (INF)Îł-activated M1-like macrophages derived from human blood monocytes. In contrast, archazolid failed to elevate TNFα production from uncommitted (M0) or interleukin (IL)-4-treated M2-like macrophages. Secretion of other relevant cytokines (i.e., IL-1ÎČ, IL-6, IL-10) or chemokines (i.e. IL-8 and monocyte chemotactic protein-1) from M1 was not affected by archazolid. Though V-ATPase inhibitors elevated the lysosomal pH in M1 comparable to chloroquine or ammonium chloride, the latter agents suppressed TNFα secretion. Archazolid selectively increased TNFα mRNA levels, which was abolished by dexamethasone. Interestingly, archazolid enhanced the phosphorylation and nuclear translocation of the p65 subunit of NFÎșB and stimulated phosphorylation of SAPK/JNK. In a microfluidically-supported human tumor biochip model, archazolid-treated M1 significantly reduced tumor cell viability. Together, our data show that V-ATPase inhibition selectively upregulates TNFα production in classically-activated macrophages along with NFÎșB and SAPK/JNK activation. Such increased TNFα release caused by V-ATPase inhibitors may contribute to tumor suppression in addition to direct targeting cancer cells
Measuring Phagocytosis of <em>Aspergillus fumigatus</em> Conidia by Human Leukocytes using Flow Cytometry
Performance, clinical effectiveness, and safety of immunoadsorption in a wide range of indications
Immunoadsorption is wellâknown to selectively remove immunoglobulins and immune complexes from plasma and is applied in a variety of autoimmune diseases and for desensitization before, or at acute rejection after organ transplantation. Performance, safety, and clinical effectiveness of immunoadsorption were the aim of this study. This prospective, noninterventional, multicentre cohort study included patients treated with immunoadsorption (Immunosorba or GLOBAFFIN adsorbers) for any indication. Clinical effectiveness was assessed after termination of the patient's individual treatment schedule. Eightyâone patients were included, 69 were treated with Immunosorba, 11 with GLOBAFFIN, one patient with both adsorbers. A majority of patients was treated for neurological indications, dilated cardiomyopathy, and before or after kidney or heart transplantation. Mean IgG reduction from preâ to postâtreatment was 69.9%â±â11.5% for Immunosorba and 74.1%â±â5.0% for GLOBAFFIN, respectively. The overall IgG reduction over a complete treatment block was 68%â93% with Immunosorba and 62%â90% with GLOBAFFIN depending on the duration of the overall treatment. After termination of the immunoadsorption therapy, an improvement of clinical status was observed in 63.0%, stabilization of symptoms in 29.6%, and a deterioration in 4.9% of patients. Changes in fibrinogen, thrombocytes, and albumin were mostly classified as noncritical. Overall, the treatments were wellâtolerated. Immunoadsorption in routine clinical practice with both GLOBAFFIN and Immunosorba has been safely performed, was well tolerated by patients, and effective in lowering immunoglobulins with an improvement or maintenance of clinical status, thus represents an additional therapeutic option for therapy refractory immune disorders