Different degree of antibody response to hepatitis B virus vaccine in breast- and formula-fed infants born to HBsAg-positive mothers

Antibody response to hepatitis B virus vaccine was compared in 47 breast- and 112 formula-fed infants born to hepatitis B surface antigen-(HBsAg-) positive mothers. No difference was observed as to the percentage of infants who seroconverted. However, formula-fed infants developed transient but significantly higher anti-HBs antibody levels as compared to breast-fed infants. Suppressive factors in human milk or orally induced tolerance may explain this finding. The latter hypothesis may be supported by the presence of HBsAg in more than half of the milk samples we studied.     

Influence of cigarette smoking on pituitary and sex hormone balance in healthy premenopausal women

Plasma gonadotropin FSH and LH, PRL, sex steroids (17-beta E2, E1, and P), SBP binding capacity, and urine estrogens (E1, E2, and E3) were measured in 485 premenopausal healthy women, subdivided according to smoking habits. The aim of the study was to verify if cigarette smoking influences sex hormone balance. Baseline PRL levels were significantly lower (P less than 0.002) in smoker (n = 174) than in nonsmoker (n = 311) women. No difference was found in the other parameters of the two groups, particularly in plasma and urine estrogenic pattern. Our data suggest that smoking directly affects PRL levels by involving the hypothalamic mechanism that regulates PRL secretion.     

Resiniferatoxin-type phorboid vanilloids display capsaicin-like selectivity at native vanilloid receptors on rat DRG neurons and at the cloned vanilloid receptor VR1.

1 Although the cloned rat vanilloid receptor VR1 appears to account for both receptor binding and calcium uptake, the identification of vanilloids selective for one or the other response is of importance because these ligands may induce distinct patterns of biological activities. 2 Phorbol 12,13-didecanoate 20-homovanillate (PDDHV) evoked 45Ca(2+)-uptake by rat dorsal root ganglion neurons (expressing native vanilloid receptors) in culture with an EC50 of 70 nM but inhibited [3H]-resiniferatoxin (RTX) binding to rat dorsal root ganglion membranes with a much lower potency (Ki>10,000 nM). This difference in potencies represents a more than 100 fold selectivity for capsaicin-type pharmacology. 3 45Ca2+ influx by PDDHV was fully inhibited by the competitive vanilloid receptor antagonist capsazepine, consistent with the calcium uptake occurring via vanilloid receptors. 4 PDDHV induced calcium mobilization in CHO cells transfected with the cloned rat vanilloid receptor VR1 with an EC50 of 125 nM and inhibited [3H]-RTX binding to these cells with an estimated Ki of 10,000 nM. By contrast, PDDHV failed to evoke a measurable calcium response in non-transfected CHO cells, confirming its action through VR1. 5 We conclude that PDDHV is two orders of magnitude more potent for inducing calcium uptake than for inhibiting RTX binding at vanilloid receptors, making this novel vanilloid a ligand selective for capsaicin-type pharmacology. These results emphasize the importance of monitoring multiple endpoints for evaluation of vanilloid receptor structure-activity relations. Furthermore, PDDHV now provides a tool to explore the biological correlates of capsaicin-type vanilloid pharmacology.     

Calcium ionophoretic and apoptotic effects of ferutinin in the human Jurkat T-cell line

We have investigated the ionophoretic and apoptotic properties of the daucane sesquiterpene ferutinin and three related compounds, ferutidin, 2-alpha-hydroxyferutidin and teferin, all isolated from various species of plants from the genus Ferula. Ferutinin induced a biphasic elevation of intracellular Ca2+ in the leukemia T-cell line, Jurkat. First, a rapid calcium peak was observed and inhibited by BAPTA-AM. This initial calcium mobilization was followed by a sustained elevation, mediated by the entry of extracellular calcium through L-type calcium channels and sensitive to inhibition by EGTA. Moreover, ferutinin-induced apoptosis in Jurkat cells, and this event was preceded, in a cyclosporine-A sensitive manner, by a loss of mitochondrial transmembrane potential (DeltaPsim) and by an increase in intracellular reactive oxygen species. Ferutinin-induced DNA fragmentation was mediated by a caspase-3-dependent pathway, and was initiated independently of any specific phase of the cell cycle. The evaluation of ferutinin analogs in calcium mobilization and apoptosis assays showed strict structure-activity relationships, with p-hydroxylation of the benzoyl moiety being requested for activity.     

Immunosuppressive activity of capsaicinoids: capsiate derived from sweet peppers inhibits NF-kappaB activation and is a potent antiinflammatory compound in vivo

Capsiate and its dihydroderivatives are the major capsaicinoids of sweet pepper. These new capsaicinoids do not activate the vanilloid receptor type 1 (VR1) but they share with capsaicin (CPS)some biological activities mediated in a VR1-independent fashion. In this study we show that CPS and nordihydrocapsiate (CPT) inhibit early and late events in T cell activation, including CD69, CD25 and ICAM-1 cell surface expression, progression to the S phase of the cell cycle and proliferation in response to TCR and CD28 co-engagement. Moreover, both CPS and CPT inhibit NF-kappaB activation in response to different agents including TNF-alpha. CPS itself does not affect the DNA-binding ability of NF-kappaB but it prevents IkappaB kinase activation and IkappaBalpha degradation in a dose-dependent manner, without inhibiting the activation of the mitogen-activated protein kinases, p38, extracellular regulated kinase and c-Jun N-terminal protein kinase. Moreover, intraperitoneal pretreatment with CPT prevented mice from lethal septic shock induced by lipopolysaccharide. In a second model of inflammation CPT pretreatment greatly reduced the extensive damage in the glandular epithelium observed in the bowel of DSS-treated mice. Taken together, these results suggest that CPT and related synthetic analogues target specific pathways involved in inflammation, and hold considerable potential for dietary health benefits as well as for pharmaceutical development.     

Ligustilide: a novel TRPA1 modulator

TRPA1 is activated by electrophilic compounds such as mustard oil (MO). Here, we demonstrate a bimodal sensitivity of TRPA1 to ligustilide (Lig), an electrophilic volatile dihydrophthalide of dietary and medicinal relevance. Lig is a potent TRPA1 activator and is also capable to induce a modest block of MO activated currents. Aromatization to dehydroligustilide (DH-Lig), as occurs during aging of its botanical sources, reversed this profile, enhancing TRPA1 inhibition and reducing activation. Mutation of the reactive cysteines in mouseTRPA1 (C622S, C642S, C666S) dramatically reduced activation by MO and significantly reduced that by Lig, but had an almost negligible effect on the action of DH-Lig, whose activation mechanism of TRPA1 is therefore largely independent from the alkylation of cysteine residues. Taken together, these observations show that the phthalide structural motif is a versatile platform to investigate the modulation of TRPA1 by small molecules, being tunable in terms of activation/inhibition profile and mechanism of interaction. Finally, the action of Lig on TRPA1 may contribute to the gustatory effects of celery, its major dietary source, and to the pharmacological action of important plants from the Chinese and native American traditional medicines.     

Anti-inflammatory and vascularprotective properties of 8-prenylapigenin

Flavonoids display several biological activities, but exhibit poor oral absorption and rapid metabolism. To improve their pharmacological profile four C8-prenyl flavonoids, structurally related to the anti-inflammatory lead apigenin, were synthesized, and the two least cytotoxic (IC₅₀  > 30 μM) compounds [8-prenylnaringenin (8-PN) and 8-prenylapigenin (8-PA)] in RAW 264.7 murine macrophages were assayed against a panel of biological targets. The anti-inflammatory properties of these compounds were evaluated in an in vitro model of inflammation [cells exposed to 0.1 μg/ml lipopolysaccharide (LPS) for 24 h]. Both 8-PN and 8-PA were equally effective and potent in inhibiting the LPS-induced gene expression [tumor necrosis factor (TNF)-α, inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2] (RT-PCR) and release (ELISA) of pro-inflammatory mediators [TNF-α, NO, prostaglandin (PG)E₂], through mechanisms involving the inhibition of nuclear factor-κB (NF-κB) activation (EMSA) and reactive oxygen species accumulation [2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) determination]. One-digit nM concentrations of 8-PN or 8-PA induced a significant increase in the basal production of the atheroprotective prostacyclin (PGI₂) by human umbilical vein endothelial cells (HUVEC), with maximal effects at 10 nM. Both NS-398, a specific COX-2 inhibitor, and ICI 182 780, a non-selective estrogen receptor antagonist, abolished the activity of these compounds, suggesting a COX- and estrogen receptor-dependent mechanism of activity. 8-PA, a weaker estrogenic compound than 8-PN, resulted only 2-fold less potent than 8-PN in potentiating PGI₂ production by HUVEC, qualifying this C8-prenyl flavonoid as a lead for the rational design of new anti-inflammatory and vascularprotective compounds.     

A multicenter observational study on Medication-Related Osteonecrosis of the Jaw (MRONJ) in advanced cancer and myeloma patients of a cancer network in North-Western Italy

Background Incidence of Medication-Related Osteonecrosis of the Jaw (MRONJ) related to cancer and myeloma treatments is undetermined, with scarce data varying from 2 to 7.8/million/year in limited investigated populations. A 9-years [2009-2018] regional-wide survey was conducted, deploying the North-Western Italy Cancer Network (“Rete Oncologica Piemonte e Valle d’Aosta”), to assess number and main characteristics of MRONJ cases among myeloma/cancer patients, within a population of 4.5 million inhabitants. Material and Methods MRONJ cases were collected retrospectively from January 2009 to June 2015; from July 2015 to December 2018, data were collected prospectively. Number of new MRONJ cases per year, underlying disorder, drug(s) administered, treatment duration, site and onset timing of MRONJ were detailed. Results 459 MRONJ cases were identified. Primary diseases were breast cancer (46%), prostate cancer (21%), myeloma (19%), and other types of carcinoma (14%). Patients received antiresorptive treatment either alone (399; 88.47%) or in combination with biological agents (52; 11.53%); 8 patients (1.7%) received only antiangiogenic drugs. Zoledronic acid [388] and denosumab [59] were the most frequently administered drugs. Mandible was involved in 296 (64,5%) cases. Number of new MRONJ cases was stable from 2009 to 2015, with a mean of 51.3 cases per year (raw incidence: 11.6/million/year), declining in the 2016-2018 years to 33.3 cases per year (raw incidence: 7.5/million/year). Conclusions With such discrepancy of cases overtime being partially explicable, number of new MRONJ cases per year are consistent with those observed in a previous study [2003-2008] in the same region, being instead higher than those reported in other populations. Key words:Osteonecrosis of the jaw, bisphosphonates, zoledronic acid, denosumab, antiangiogenic drug, incidence.