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Author(s): Veronika Souslova; Paolo Cesare; Yanning Ding; Armen N. Akoplan; Louise Stanfa; Rie Suzuki; Katherine Carpenter; Daniela Nebenius-Oosthuizen; Andrew J. H. Smith; Emma J. Kidd; John N. Wood Nature 407 [...]

Trace amines, including tyramine and β-phenylethylamine (β-PEA), are constituents of many foods including chocolate, cheeses and wines and are generated by so-called ‘friendly’ bacteria such as Lactobacillus, Lactococcus and Enterococcus species, which are found in probiotics. We therefore examined whether these dietary amines could exert pharmacological effects on the gut and its vasculature. In the present study we examined the effects of tyramine and β-PEA on the contractile activity of guinea-pig and rat ileum and upon the isolated mesenteric vasculature and other blood vessels. Traditionally, these amines are regarded as sympathomimetic amines, exerting effects through the release of noradrenaline from sympathetic nerve endings, which should relax the gut. A secondary aim was therefore to confirm this mechanism of action. However, contractile effects were observed in the gut and these were independent of noradrenaline, acetylcholine, histamine and serotonin receptors. They were therefore probably due to the recently described trace amine-associated receptors. These amines relaxed the mesenteric vasculature. In contrast, the aorta and coronary arteries were constricted, a response that was also independent of a sympathomimetic action. From these results, we propose that after ingestion, trace amines could stimulate the gut and improve intestinal blood flow. Restriction of blood flow elsewhere diverts blood to the gut to aid digestion. Thus, trace amines in the diet may promote the digestive process through stimulation of the gut and improved gastrointestinal circulation. [ABSTRACT FROM PUBLISHER]

The P2X[sub7] cell surface receptor is responsible for adenosine triphosphate-dependent lysis of immune cells following the formation of non-selective membrane pores. This study examined changes in P2X[sub7] receptor distribution following agonist treatment. Human THP-1 monocytes were exposed to the agonist 2′-3′-O-(4-benzoylbenzoyl) adenosine 5′-triphosphate for 1—40 min after which P2X[sub7] receptors were immunogold labelled. The number and distribution of P2X7 receptors on the cell membrane were quantified using transmission electron microscopy. Increasing the time of agonist exposure resulted in clustering of P2X[sub7] receptors, a decrease in individual P2X[sub7] receptors and no change in the total number of P2X[sub7] receptors. These results suggest that pore formation does not involve further insertion or initial movement of receptors in the membrane but that P2X[sub7] receptors do cluster together after prolonged activation. [ABSTRACT FROM AUTHOR]

Adenosine 5′-triphosphate (ATP) is known to play a significant role as a neurotransmitter in smooth muscle. There is evidence to show that ATP can cause bladder contractions and may also be involved in the processing of sensory information in the urinary bladder. These effects are likely to be mediated by P2X receptors, namely P2X[sub 1] and P2X[sub 3] , respectively. This study set out to investigate their distribution in rat and human urinary bladders. P2X[sub 1] receptor immunoreactivity was found on detrusor muscle fibres and P2X[sub 3] receptor immunoreactivity was found in the urothelium of both species. This is the first demonstration of a non-neuronal localisation for P2X[sub 3] receptors. No clear evidence was found for the presence of P2X[sub 3] receptors on calcitonin gene-related peptide-containing sensory nerves and therefore P2X[sub 3] receptors may not have a direct role in the mediation of sensory responses to ATP in the urinary bladder.Copyright © 2001 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Age is the biggest risk factor for Alzheimer's disease (AD) with cases doubling every 5 years after 65 years. Increased risk is also associated with being female. This gender difference in AD incidence could be partly explained by menopause‐related hormone deficiencies during ageing. Clinical studies concluded that the age when hormone replacement therapy was started, especially after the menopause, was critical in delaying AD development. Deposition of b‐amyloid (Ab) in the hippocampus and cortex is the key pathological feature in AD. Much evidence has demonstrated that oestrogen activation of oestrogen receptors (ER) in neurones decreases Ab accumulation and antagonizes its cytotoxic effects in AD. ERb is an ER subtype highly expressed in the nervous system. In vivo studies reported that ERb activation reduces the cytotoxic effect of Ab through the Akt pathway and improves learning and memory capacity in AD models. However, this finding has not yet been investigated in the clinic. We hypothesised that the increased risk of AD in women could be partly explained by alterations in the levels of oestrogen, its receptors and downstream signalling pathways in the female brain during ageing affecting the expression of AD biomarkers. Method: Levels of ERb, phosphorylated and total Akt, APP, its secretases and metabolites were measured using immunoblotting and ELISA in frontal cortical brain samples from young (20‐30), middle‐aged (45‐55) and old (70‐90) men and women with no history of dementia. Result: In female brains significant age‐related increases in APP and the secretases were observed but were not seen in male samples. bCTF and the Aβ42:40 ratio also showed age‐related increases only in women. Aβ42 levels were higher in elderly female samples compared to male. In contrast, significant age‐related increases in ERb and pAkt:total Akt were only seen in male samples. Conclusion: We demonstrate for the first time a sex difference in the expression of AD biomarkers with ageing with a novel age‐related increase in APP in the ageing female brain. The increase in ERb expression in male but not female samples could result in a neuroprotective effect against Aβ cytotoxicity. Our findings could partly explain female vulnerability for AD development. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is a highly complex and multifactorial neurodegenerative disorder, with age being the most significant risk factor. The incidence of Alzheimer's disease doubles every 5 years after the age of 65. Consequently, one of the major challenges in Alzheimer's disease research is understanding how the brain changes with age. Gaining insights into these changes could help identify individuals who are more prone to developing Alzheimer's disease as they age. Over the past 25 years, studies on brain aging have examined thousands of human brains to explore the neuronal basis of age-related cognitive decline. However, most of these studies have focused on adults over 60, often neglecting the critical menopause transition period. During menopause, women experience a substantial decline in ovarian sex hormone production, with a decrease of about 90% in estrogen levels. Estrogen is known for its neuroprotective effects, and its significant loss during menopause affects various biological systems, including the brain. Importantly, despite known differences in dementia risk between sexes, the impact of biological sex and sex hormones on brain aging and the development of Alzheimer's disease remains underexplored., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Lipopolysaccharide (LPS) contributes to asthma exacerbations and development of inhaled corticosteroid insensitivity. Complete resistance to systemic corticosteroids is rare, and most patients lie on a continuum of steroid responsiveness. This study aimed to examine the sensitivity of combined ovalbumin- (Ova) and LPS-induced functional and inflammatory responses to inhaled and systemic corticosteroid in conscious guinea pigs to test the hypothesis that the route of administration affects sensitivity. Guinea pigs were sensitized to Ova and challenged with inhaled Ova alone or combined with LPS. Airway function was determined by measuring specific airway conductance via whole-body plethysmography. Airway hyper-responsiveness to histamine was determined before and 24 hours post-Ova challenge. Airway inflammation and underlying mechanisms were determined from bronchoalveolar lavage cell counts and lung tissue cytokines. Vehicle or dexamethasone was administered by once-daily i.p. injection (5, 10, or 20 mg/kg) or twice-daily inhalation (4 or 20 mg/ml) for 6 days before Ova challenge or Ova with LPS. LPS exacerbated Ova-induced responses, elongating early asthmatic responses (EAR), prolonging histamine bronchoconstriction, and further elevating airway inflammation. Intraperitoneal dexamethasone (20 mg/kg) significantly reduced the elongated EAR and airway inflammation but not the increased bronchoconstriction to histamine. In contrast, inhaled dexamethasone (20 mg/ml), which inhibited responses to Ova alone, did not significantly reduce functional and inflammatory responses to combined Ova and LPS. Combined Ova and LPS-induced functional and inflammatory responses are insensitive to inhaled, but they are only partially sensitive to systemic, dexamethasone. This finding suggests that the route of corticosteroid administration may be important in determining corticosteroid sensitivity of asthmatic responses., (Copyright © 2017 by The Author(s).)

Background: Polymorphisms in the gene for phosphatidylinositol binding clathrin assembly protein (PICALM), an endocytic-related protein, are associated with a small, increased risk of developing Alzheimer's disease (AD), strongly suggesting that changes in endocytosis are involved in the aetiology of the disease. We have investigated the involvement of PICALM in the processing of amyloid precursor protein (APP) to understand how PICALM could be linked to the development of AD. We used siRNA to deplete levels of PICALM, its isoforms and clathrin heavy chain in the human brain-derived H4 neuroglioma cell line that expresses endogenous levels of APP. We then used Western blotting, ELISA and immunohistochemistry to detect intra- and extracellular protein levels of endocytic-related proteins, APP and APP metabolites including β-amyloid (Aβ). Levels of functional endocytosis were quantified using ALEXA 488-conjugated transferrin and flow cytometry as a marker of clathrin-mediated endocytosis (CME)., Results: Following depletion of all the isoforms of PICALM by siRNA in H4 cells, levels of intracellular APP, intracellular β-C-terminal fragment (β-CTF) and secreted sAPPβ (APP fragments produced by β-secretase cleavage) were significantly reduced but Aβ40 was not affected. Functional endocytosis was significantly reduced after both PICALM and clathrin depletion, highlighting the importance of PICALM in this process. However, depletion of clathrin did not affect APP but did reduce β-CTF levels. PICALM depletion altered the intracellular distribution of clathrin while clathrin reduction affected the subcellular pattern of PICALM labelling. Both PICALM and clathrin depletion reduced the expression of BACE1 mRNA and PICALM siRNA reduced protein levels. Individual depletion of PICALM isoforms 1 and 2 did not affect APP levels while clathrin depletion had a differential effect on the isoforms, increasing isoform 1 while decreasing isoform 2 expression., Conclusions: The depletion of PICALM in brain-derived cells has significant effects on the processing of APP, probably by reducing CME. In particular, it affects the production of β-CTF which is increasingly considered to be an important mediator in AD independent of Aβ. Thus a decrease in PICALM expression in the brain could be beneficial to slow or prevent the development of AD.

The P2X(7) cell surface receptor is responsible for adenosine triphosphate-dependent lysis of immune cells following the formation of non-selective membrane pores. This study examined changes in P2X(7) receptor distribution following agonist treatment. Human THP-1 monocytes were exposed to the agonist 2'-3'-O-(4-benzoyl-benzoyl) adenosine 5'-triphosphate for 1-40 min after which P2X(7) receptors were immunogold labelled. The number and distribution of P2X(7) receptors on the cell membrane were quantified using transmission electron microscopy. Increasing the time of agonist exposure resulted in clustering of P2X(7) receptors, a decrease in individual P2X(7) receptors and no change in the total number of P2X(7) receptors. These results suggest that pore formation does not involve further insertion or initial movement of receptors in the membrane but that P2X(7) receptors do cluster together after prolonged activation., (Copyright 2003 S. Karger AG, Basel)