The function and regulation of amyloid-beta (Aβ) in healthy and diseased liver remains unexplored. Because Aβ reduces the integrity of the blood-brain barrier we have examined its potential role in regulating the sinusoidal permeability of normal and cirrhotic liver. Aβ and key proteins that generate (beta-secretase 1 and presenilin-1) and degrade it (neprilysin and myelin basic protein) were decreased in human cirrhotic liver. In culture, activated hepatic stellate cells (HSC) internalized Aβ more efficiently than astrocytes and HSC degraded Aβ leading to suppressed expression of α-smooth muscle actin (α-SMA), collagen 1 and transforming growth factor β (TGFβ). Aβ also upregulated sinusoidal permeability marker endothelial NO synthase (eNOS) and decreased TGFβ in cultured human liver sinusoidal endothelial cells (hLSEC). Liver Aβ levels also correlate with the expression of eNOS in transgenic Alzheimer’s disease mice and in human and rodent cirrhosis/fibrosis. These findings suggest a previously unexplored role of Aβ in the maintenance of liver sinusoidal permeability and in protection against cirrhosis/fibrosis via attenuation of HSC activation.

Angiotensin receptor blockers (ARBs) have demonstrated multiple neuroprotective benefits in Alzheimer’s disease (AD) models. However, their beneficial effects on memory deficits, cholinergic activity, neurogenesis and Amyloid beta (Aβ) clearance reveal significant interstudy variability. The delivery route can impact not only delivery but also targeting and therapeutic efficacy of ARBs. Our previous findings on the beneficial effects of intranasally delivered losartan in the APP/PS1 model of AD prompted us to explore the influence of the delivery route by employing here the systemic administration of losartan. Consistent with our previous results with intranasal losartan, repeated intraperitoneal administration (10 mg/kg) resulted in a remarkable decrease in Aβ plaques and soluble Aβ42, as well as inflammatory cytokines (IL-2, IL-6 and TNFα). The Aβ reduction can be ascribed to its facilitated degradation by neprilysin and diminished generation by BACE1. Losartan increased neurogenesis in vivo and in vitro and improved migratory properties of astrocytes isolated from adult transgenic AD mice. In summary, this data together with our previous results suggest therapeutic features of losartan which are independent of delivery route. The improvement of cell motility of Aβ-affected astrocytes by losartan deserves further in vivo investigation, which may lead to new strategies for AD treatment.

The present research summarizes the protective and immunomodulatory activity of hypothalamic proline-rich polypeptide galarmin against methicillin-resistant Staphylococcus aureus (MRSA). The protective effect of galarmin was shown on MRSA-infected animals' survival and weight loss recovery. The immunological impact of galarmin was evaluated in terms of immunocompetent cell recruitment, serum immunoglobulins, complement components C3 and C4, and pro- and anti-inflammatory cytokines (IL-6, IL-8, IL-10, IL-1b, TNFa, and KC) secretion. Galarmin efficiently protects mice against lethal MRSA infection (100% of survival vs. 0% in the untreated group) when intramuscularly injected 24 h before infection and during the 1-h post-infection period at a concentration of 1 μg per mouse, while its higher concentrations (5 and 10 μg) were protective when injected in parallel to the infection process. The protective effect of galarmin was not due to a direct effect on MRSA, but should be attributed to an action on the host response to infection. Galarmin significantly increased and modulated the levels of IL-6, IL-8, IL-1b, IL-10, and KC in both peritoneal lavages and blood, leukocyte and platelet counts, lymphocytes percentage, serum IgM and IgG, and complement C3 and C4 components secretion. The experimental results allow concluding that galarmin is a powerful immunomodulatory and protective agent for the in vivo prophylaxis and treatment of MRSA-induced infection.