Intestinal antispasmodic effects of three Argentinian plants: <i>Hypericum connatum</i>, <i>Berberis ruscifolia</i> and <i>Cecropia pachystachya</i>: mechanisms of action and comparison with the effects of <i>Brugmansia arborea</i>

Some medicinal plants are used in Argentina to reduce gastrointestinal symptoms as antispasmodics, but notall these effects were validated. This work studied the effects of three native plants as the ethanolic tinctures(T) of Hypericum connatum and Berberis ruscifolia, as well as the acqueous crude extracts (A.c.e) of Cecropiapachystachya, and compared the mechanisms with those of the peruvian plant Brugmansia arborea inisolated rat intestines. The first three plants demonstrated to have antispasmodic effect mainly due to thenon-competitive blockade of the agonist-induced contraction and calcium influx to the smooth muscle,which was associated to the presence of flavonoids. H. connatum also induced the release of prostaglandinswhich cause intestinal contraction, and NO which cause peristalsis, in a way that the blockade of bothmechanisms potentiated the relaxant effect of the T-H.c. In contrast, the A.c.e of Brugmansia arboreashowed to be a competitive antagonist of muscarinic receptors in the isolated intestine, in agreement withthe presence of tropane alkaloids. Moreover, H. connatum and C. pachystachya also produced certainsedation, which could contribute to the antispasmodic effect. The tincture of Hypericum connatum, but notthat of Berberis ruscifolia, reduced the spontaneous locomotion and exploration of mice in the open-fieldtest, at doses of 200 mg leaves/Kg. Results suggest that the three native plants exhibited an importantantispasmodic effect mainly due to non-competitive antagonism of the agonist and of Ca2+-influx to smoothmuscle.Facultad de Ciencias Exacta

Intestinal antispasmodic effects of three Argentinian plants: <i>Hypericum connatum</i>, <i>Berberis ruscifolia</i> and <i>Cecropia pachystachya</i>: mechanisms of action and comparison with the effects of <i>Brugmansia arborea</i>

Some medicinal plants are used in Argentina to reduce gastrointestinal symptoms as antispasmodics, but notall these effects were validated. This work studied the effects of three native plants as the ethanolic tinctures(T) of Hypericum connatum and Berberis ruscifolia, as well as the acqueous crude extracts (A.c.e) of Cecropiapachystachya, and compared the mechanisms with those of the peruvian plant Brugmansia arborea inisolated rat intestines. The first three plants demonstrated to have antispasmodic effect mainly due to thenon-competitive blockade of the agonist-induced contraction and calcium influx to the smooth muscle,which was associated to the presence of flavonoids. H. connatum also induced the release of prostaglandinswhich cause intestinal contraction, and NO which cause peristalsis, in a way that the blockade of bothmechanisms potentiated the relaxant effect of the T-H.c. In contrast, the A.c.e of Brugmansia arboreashowed to be a competitive antagonist of muscarinic receptors in the isolated intestine, in agreement withthe presence of tropane alkaloids. Moreover, H. connatum and C. pachystachya also produced certainsedation, which could contribute to the antispasmodic effect. The tincture of Hypericum connatum, but notthat of Berberis ruscifolia, reduced the spontaneous locomotion and exploration of mice in the open-fieldtest, at doses of 200 mg leaves/Kg. Results suggest that the three native plants exhibited an importantantispasmodic effect mainly due to non-competitive antagonism of the agonist and of Ca2+-influx to smoothmuscle.Facultad de Ciencias Exacta

Intestinal antispasmodic effects of three Argentinian plants: <i>Hypericum connatum</i>, <i>Berberis ruscifolia</i> and <i>Cecropia pachystachya</i>: mechanisms of action and comparison with the effects of <i>Brugmansia arborea</i>

Some medicinal plants are used in Argentina to reduce gastrointestinal symptoms as antispasmodics, but notall these effects were validated. This work studied the effects of three native plants as the ethanolic tinctures(T) of Hypericum connatum and Berberis ruscifolia, as well as the acqueous crude extracts (A.c.e) of Cecropiapachystachya, and compared the mechanisms with those of the peruvian plant Brugmansia arborea inisolated rat intestines. The first three plants demonstrated to have antispasmodic effect mainly due to thenon-competitive blockade of the agonist-induced contraction and calcium influx to the smooth muscle,which was associated to the presence of flavonoids. H. connatum also induced the release of prostaglandinswhich cause intestinal contraction, and NO which cause peristalsis, in a way that the blockade of bothmechanisms potentiated the relaxant effect of the T-H.c. In contrast, the A.c.e of Brugmansia arboreashowed to be a competitive antagonist of muscarinic receptors in the isolated intestine, in agreement withthe presence of tropane alkaloids. Moreover, H. connatum and C. pachystachya also produced certainsedation, which could contribute to the antispasmodic effect. The tincture of Hypericum connatum, but notthat of Berberis ruscifolia, reduced the spontaneous locomotion and exploration of mice in the open-fieldtest, at doses of 200 mg leaves/Kg. Results suggest that the three native plants exhibited an importantantispasmodic effect mainly due to non-competitive antagonism of the agonist and of Ca2+-influx to smoothmuscle.Facultad de Ciencias Exacta

Activation of acid sphingomyelinase and its inhibition by the nitric oxide/cyclic guanosine 3&#8242;,5&#8242;-monophosphate pathway: Key events in Escherichia coli-elicited apoptosis of dendritic cells

Depletion of dendritic cells (DCs) via apoptosis contributes to sepsis-induced immune suppression. The mechanisms leading to DC apoptosis during sepsis are not known. In this study we report that immature DCs undergo apoptosis when treated with high numbers of Escherichia coli. This effect was mimicked by high concentrations of LPS. Apoptosis was accompanied by generation of ceramide through activation of acid sphingomyelinase (A-SMase), was prevented by inhibitors of this enzyme, and was restored by exogenous ceramide. Compared with immature DCs, mature DCs expressed significantly reduced levels of A-SMase, did not generate ceramide in response to E. coli or LPS, and were insensitive to E. coli- and LPS-triggered apoptosis. However, sensitivity to apoptosis was restored by addition of exogenous A-SMase or ceramide. Furthermore, inhibition of A-SMase activation and ceramide generation was found to be the mechanism through which the immune-modulating messenger NO protects immature DCs from the apoptogenic efects of E. coli and LPS. NO acted through formation of cGMP and stimulation of the cGMP-dependent protein kinase. The relevance of A-SMase and its inhibition by NO/cGMP were confirmed in a mouse model of LPS-induced sepsis. DC apoptosis was significantly higher in inducible NO synthase-deficient mice than in wild-type animals and was significantly reduced by treatment ex vivo with NO, cGMP, or the A-SMase inhibitor imipramine. Thus, A-SMase plays a central role in E. coli/LPS-induced DC apoptosis and its inhibition by NO, and it might be a target of new therapeutic approaches to sepsis

Synergism of nitric oxide and maturation signals on human dendritic cells occurs through a cyclic GMP-dependent pathway

Nitric oxide (NO), generated by phagocytes at inflammation sites, contributes to regulate immune responses through autocrine and paracrine actions on bystander cells. Among the latter are dendritic cells (DCs). Little is known about regulation of DC function by NO, especially in the human system. We exposed human monocyte-derived DCs to the NO donor (z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino] diazen-1-ium-1,2 diolate (DETA-NO) during their maturation process induced by treatment with tumor necrosis factor alpha or lipopolysaccharide or by CD40 activation. We report here that after exposure to DETA-NO, DCs exhibit a significantly increased ability to activate T lymphocytes stimulated by mycobacterial antigens, Staphylococcus aureus Cowen strain B, allo-antigens, or cross-linking of the CD3-T cell receptor complex. This effect persists after removal of DETA-NO, depends on the generation of cyclic guanosine 5'-monophosphate, and is a result of enhanced release by DCs of soluble factors, in particular interleukin (IL)-12. This modulation of DC function is a result of a synergism between NO and the various maturation stimuli, as neither enhanced T cell activation nor IL-12 release was observed after DC exposure to DETA-NO only. These results provide the first evidence that NO acts as a cosignaling molecule regulating human DC response to maturation stimuli

Nitric oxide confers therapeutic activity to dendritic cells in a mouse model of melanoma

Susceptibility of dendritic cells (DCs) to tumor-induced apoptosis reduces their efficacy in cancer therapy. Here we show that delivery within exponentially growing B16 melanomas of DCs treated ex vivo with nitric oxide (NO), released by the NO donor (z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NO), significantly reduced tumor growth, with cure of 37% of animals. DETA-NO-treated DCs became resistant to tumor-induced apoptosis because DETA-NO prevented tumor-induced changes in the expression of Bcl-2, Bax, and Bcl-xL; activation of caspase-9; and a reduction in the mitochondrial membrane potential. DETA-NO also increased DC cytotoxic activity against tumor cells and DC ability to trigger T-lymphocyte proliferation. All of the effects of DETA-NO were mediated through cGMP generation. NO and NO-generating drugs may therefore be used to increase the anticancer efficacy of DCs

Corrigendum to: Comparative study of obstetric antiphospholipid syndrome (OAPS) and non-criteria obstetric APS (NC-OAPS): report of 1640 cases from EUROAPS registry

Rheumatology 2020;59:1306–1314. doi:https://doi.org/10.1093/rheumatology/kez419 In the original article, the affiliation of co-author Cecilia Beatrice Chighizola should have read: “Experimental Laboratory of Immunological and Rheumatologic Researches, Istituto Auxologico Italiano, IRCCS, Cusano Milanino, Milan, Italy”. These details have been corrected only in this corrigendum to preserve the published version of record

Chromogranin-A production and fragmentation in patients with Takayasu arteritis

BACKGROUND: Chromogranin-A (CgA) is a secretory protein processed into peptides that regulate angiogenesis and vascular cells activation, migration and proliferation. These processes may influence arterial inflammation and remodelling in Takayasu arteritis (TA). METHODS: Plasma levels of full-length CgA (CgA439), CgA fragments lacking the C-terminal region (CgA-FRs) and the N-terminal fragment, CgA1-76 (vasostatin-1, VS-1) were analysed in 42 patients with TA and 20 healthy age-matched controls. Vascular remodelling was longitudinally assessed by imaging. CgA peptides were related to markers of systemic and local inflammation, disease activity and vascular remodelling. RESULTS: Levels of CgA-FRs and VS-1 were increased in TA. Treatment with proton-pump inhibitors (PPIs) and arterial hypertension partially accounted for CgA levels and high inter-patient variability. CgA439, CgA-FRs and VS-1 levels did not reflect disease activity or extent. Markers of systemic or local inflammation correlated with higher CgA-FRs and VS-1 in normotensive patients and with higher CgA439 in hypertensive patients. Treatment with non-biologic anti-rheumatic agents was associated with increased CgA-FRs and a distinctive regulation of CgA processing. Reduced blood levels of anti-angiogenic CgA peptides were associated with vascular remodelling in the groups of patients on PPIs and with arterial hypertension. CONCLUSIONS: The plasma levels of CgA fragments are markedly increased in TA as a consequence of disease- and therapy-related variables. Anti-angiogenic forms of CgA may limit vascular remodelling. Given the effect of the various CgA peptides, it is advisable to limit the therapeutic prescriptions that might influence CgA-derived peptide levels to clearly agreed medical indications until further data become available

Oxidation of HMGB1 Causes Attenuation of Its Pro-Inflammatory Activity and Occurs during Liver Ischemia and Reperfusion

High mobility group box 1 (HMGB1) is a nuclear transcription factor. Once HMGB1 is released by damaged cells or activated immune cells, it acts as danger molecule and triggers the inflammatory signaling cascade. Currently, evidence is accumulating that posttranslational modifications such as oxidation may modulate the pro-inflammatory potential of danger signals. We hypothesized that oxidation of HMGB1 may reduce its pro-inflammatory potential and could take place during prolonged ischemia and upon reperfusion

Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6,809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+ ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA