Antioxidant activity and inhibitory effect of Gamazumi (Viburnum dilatatum THUNB.) on oxidative damage induced by water immersion restraint stress in rats

The antioxidant activity and antiulcer effects of Gamazumi (Viburnum dilatatum THUNB.) fruit squeezing solution (GSS) were investigated. GSS including no antioxidant additive showed strong antioxidant activity by the XYZ-dish method and the electron spin resonance (ESR) method. GSS showed to have no negative effect on growth of rats for 2 weeks of feeding with free access to GSS. After feeding, the GSS group showed a significant inhibitory effect on gastric ulcer formation by water immersion restraint stress for 6 hours compared with the Water group. Plasma, liver and stomach concentrations of lipid peroxide in the GSS group were reduced rather than the water group. Furthermore, the activities of plasma lactic dehydrogenase, amylase and creatine phosphokinase are ordinarily increased by stress; however these activities in the GSS group decreased to the level in the Control group having no stress. The physiological effects of GSS were similar to, or higher than, those of 0.1% (-)-epigallocatechin gallate (EGCg) solution. These effects of EGCg and GSS were similar to the order of antioxidant activity against hydroxyl radical found by both the XYZ-dish and the ESR methods. It was concluded that after ingestion of GSS, during the period of strong antioxidant activity in the body, it could prevent stress-induced oxidative damage.     

Mast cells mediate neutrophil recruitment and vascular leakage through the NLRP3 inflammasome in histamine-independent urticaria

Urticarial rash observed in cryopyrin-associated periodic syndrome (CAPS) caused by nucleotide-binding oligomerization domain–leucine-rich repeats containing pyrin domain 3 (NLRP3) mutations is effectively suppressed by anti–interleukin (IL)-1 treatment, suggesting a pathophysiological role of IL-1β in the skin. However, the cellular mechanisms regulating IL-1β production in the skin of CAPS patients remain unclear. We identified mast cells (MCs) as the main cell population responsible for IL-1β production in the skin of CAPS patients. Unlike normal MCs that required stimulation with proinflammatory stimuli for IL-1β production, resident MCs from CAPS patients constitutively produced IL-1β. Primary MCs expressed inflammasome components and secreted IL-1β via NLRP3 and apoptosis-associated speck-like protein containing a caspase recruitment domain when stimulated with microbial stimuli known to activate caspase-1. Furthermore, MCs expressing disease-associated but not wild-type NLRP3 secreted IL-1β and induced neutrophil migration and vascular leakage, the histological hallmarks of urticarial rash, when transplanted into mouse skin. Our findings implicate MCs as IL-1β producers in the skin and mediators of histamine-independent urticaria through the NLRP3 inflammasome.Urticaria, or hives, is a common disease that can affect up to 20% of the general population (1). Chronic urticaria, defined as urticaria that persists for >6 wk, occurs in 0.1% of the population (2), and in a significant percentage of cases (∼40–80%), there is no identifiable cause (1, 3). H1 antihistamines have remained the first line of treatment because histamine release from cutaneous mast cells (MCs) plays an important role in the pathophysiology of urticaria development. However, only ∼55% of patients with chronic urticaria are responsive to antihistamines (4), suggesting that in a significant number of individuals, chronic urticaria is mediated via histamine-independent mechanisms.An urticarial rash developing in the neonatal or early infantile period is one of the clinical manifestations characteristic of cryopyrin-associated periodic syndrome (CAPS). CAPS consists of a spectrum of hereditary periodic fever disorders that comprise three phenotypically overlapping but relatively distinct syndromes: familial cold autoinflammatory syndrome (Mendelian inheritance in men number [MIM] 120100), Muckle-Wells syndrome (MWS; MIM 191900), and chronic infantile neurological cutaneous and articular syndrome (MIM 607115), which is also known as neonatal-onset multisystem inflammatory disease. Familial cold autoinflammatory syndrome and MWS are characterized by periodic attacks of urticarial rash, fever, and arthralgia, whereas patients with chronic infantile neurological cutaneous and articular syndrome, the most severe form of CAPS, exhibit chronic urticaria as well as fever, arthropathy, chronic meningitis, papilledema, growth and mental retardation, and hearing loss (5). The urticarial rash observed in CAPS is similar to that associated with common urticaria. However, unlike the latter disorder, the rash observed in most CAPS patients responds to therapy with IL-1 receptor antagonist rather than antihistamines, suggesting that urticaria in these patients is mediated by IL-1. However, the cellular mechanism responsible for urticaria in CAPS patients remains poorly understood.The mature form of IL-1β is produced by cleavage of the inactive pro–IL-1β precursor by caspase-1, a protease activated by a large multiprotein complex termed the inflammasome (6). CAPS is caused by missense mutations in the gene, nucleotide-binding oligomerization domain (NOD)–leucine-rich repeats (LRRs) containing pyrin domain 3 (NLRP3) (7), whose product is a component of the inflammasome that includes the adaptor protein, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and procaspase-1 (8, 9). NLRP3, a member of the NOD-like receptor family, is an intracellular receptor involved in the recognition of pathogen-associated molecular patterns (PAMPs). Although several microbial activators of NLRP3 have been reported, the precise mechanism by which the NLRP3 inflammasome is activated by PAMPs remains poorly understood. In the presence of ATP or pore-forming molecules, several PAMPs, including LPS, muramyl dipeptide, bacterial mRNA, and the antiviral compound R837, activate the NLRP3 inflammasome (10, 11). In addition to PAMPs, NLRP3 senses endogenous danger signals such as monosodium urate crystals and particulate matter including asbestos, silica (12), and aluminum salts (13, 14). Disease-associated NLRP3 mutations associated with CAPS localize to the centrally located NOD domain and constitutively activate caspase-1 to produce active IL-1β (8, 15). NLRP3 is predominantly expressed in monocytes, granulocytes, and chondrocytes (16, 17), but to date, no reports have investigated the cells in the skin that are involved in the development of urticarial rash associated with CAPS. Our study identifies resident MCs in the skin as a cell population capable of producing IL-1β via the NLRP3 inflammasome and provides evidence that MCs mediate urticarial rash via dysregulated IL-1β production in the skin of CAPS patients.     

A case of giant cell arteritis with massive pericardial effusion

Giant cell arteritis (GCA) is a chronic inflammatory disease of the medium and large blood vessels. The early symptoms of this disease are nonspecific, and pericardial effusion is a rare manifestation of GCA. Recently, we investigated a case of GCA in which massive pericardial effusion was the initial symptom, and active aortitis was observed on positron emission tomography with fluorine-18 fluorodeoxyglucose. These observations indicated that pericardial effusion could occur in patients with GCA.